Recent advanced lipid-based nanomedicines for overcoming cancer resistance
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Abstract
The increasing prevalence of cancer drug resistance not only critically limits the efficiency of traditional therapies but also causes relapses or recurrences of cancer. Consequently, there remains an urgent need to address the intricate landscape of drug resistance beyond traditional cancer therapies. Recently, nanotechnology has played an important role in the field of various drug delivery systems for the treatment of cancer, especially therapy-resistant cancer. Among advanced nanomedicine technologies, lipid-based nanomaterials have emerged as effective drug carriers for cancer treatment, significantly improving therapeutic effects. Due to their biocompatibility, simplicity of preparation, and potential for functionalization, lipid-based nanomaterials are considered powerful competitors for resistant cancer. In this review, an overview of lipid-based nanomaterials for addressing cancer resistance is discussed. We summarize the recent progress in overcoming drug resistance in cancer by these lipid-based nanomaterials, and highlight their potential in future applications to reverse cancer resistance.
Keywords
INTRODUCTION
Cancer is one of the foremost causes of mortality globally. In 2023, the American Cancer Society estimated the number of new cancer cases as high as 1,958,310 in the U.S. and 609,820 cases would be accounted by cancer-related fatality, approximating 4 new cases and 1 death every minute[1]. Nowadays, combinations of surgery, radiation therapy, and chemotherapy are the standard regimen for cancer management. However, the success of the therapeutic approaches is known to be affected by off-target effects and severe drug resistance in many types of cancer such as breast cancer[2,3], lung cancer[4], colon cancer[5], and prostate cancer[6,7].
Drug resistance that the cancer cells withstand a wide range of treatments is a crucial problem in cancer management, and is associated with relapses or recurrences, significantly hindering the cure[8-12]. Based on the timing of drug resistance development, it can be divided into intrinsic resistance and acquired resistance. Intrinsic resistance exists before the beginning of therapy, which is possibly caused by tumor heterogeneity subpopulations, inherent genetic mutations, and activation of intrinsic detoxification pathways. Conversely, acquired resistance occurs after therapy, which results from post-treatment changes in tumor microenvironment (TME), activation of second proto-oncogenes or tumor suppressor genes, and mutations or alteration of drug target expression levels after treatment. Additionally, drug resistance can be clinically categorized based on specific mechanisms including tumor heterogeneity, increased efflux of drugs, enhanced DNA damage repair, altered drug target, epithelial-mesenchymal transition, and so on[12-21]. Theoretically, retaining cytotoxic agents within the cells, erasing reversible modifications, modifying the TME, and delivering combinations of cytotoxic drugs with different mechanisms to cancer cells are basic principles for circumventing cancer drug resistance. These approaches may re-sensitize the patients to the treatment[22,23].
To date, studies on treatment strategies to overcome drug resistance have been conducted for a better understanding of different resistance mechanisms. Nanotechnology-based therapy is typically referred to as medical treatments that utilize nanoscale materials and devices to diagnose, monitor, and treat disease. The products developed from this technology are referred to as nanomedicines and nanoformulations, which are materials systems consisting of appropriate nanocarriers and active pharmaceutical ingredients[24,25]. Consequently, the effective functioning of nanomedicines relies on the utilization of nanoparticles. Typically, nanoparticles are classified into three categories based on their compositions: (1) inorganic nanoparticles; (2) organic nanoparticles; and (3) hybrid nanoparticles [Figure 1A][26-29]. Numbers of studies have demonstrated the promising results of nanomaterials in nanoformulations to enhance efficiency and minimize the severe off-target effects[30-35]. The potential of nanotechnology-based therapy in anti-drug resistance strategies is attracting significant attention[23,36-39].
Figure 1. Schematic presentation. (A) classification of nanomaterials; (B) classification of lipid-based nanomaterials: lamellar NPs include liposomes, LNPs, LNEs, SLNs, NLCs, and lipid polymer hybrid NPs; (C) non-lamellar NPs include hexosomes and cubosomes; (D) typical preparation methods of lipid-based nanomaterials. (A, B and D) are created by www.BioRender.com; (C) is quoted with permission from Tan et al.[29]. NPs: Nanoparticles; LNPs: lipid nanoparticles; LNEs: lipid nanoemulsions; SLNs: solid lipid nanoparticles; NLCs: nanostructured lipid carriers.
Nanoformulations are defined by the U.S. Food and Drug Administration (FDA) as products in combination with nanoparticles having one or more dimensions ranging from 1-100 nanometers (nm) or up to 1,000 nm if the size is engineered to show specific dimension-dependent properties or phenomena[40-43]. However, there is no universally recognized definition for nanoformulations[44]. The typical size preferred in nanomedicine applications is in the range of 100-200 nm due to its ability to cross microcapillaries and capacity to accommodate an adequate amount of active pharmaceutical agents[45]. Doxil®, the first nanoformulation of doxorubicin (DOX) encapsulated in 100 nm liposomes, was approved in 1995. It remains a first-line cancer treatment to the present. The lower cardiotoxicity and enhanced efficiency in killing tumor cells of Doxil® increase chemotherapy sensitivity and diminish the drug resistance over the free drug molecule[46]. The excellent therapeutic effects demonstrated by nanoformulations compared to free drug molecules, including improved pharmacokinetics, enhanced target specificity, and reduced systemic toxicity, have garnered significant interest in the development of anticancer drugs[47]. Subsequently, robust nanomedicines have been continuously developed and approved for cancer treatment [Table 1]. It is worth noting that among nanoformulations launched on the market for clinical cancer treatment, lipid-based nanomaterials are the frontrunners[48].
| No. | Description of carrier and its compositions | Product names | Manufacturer | Indication(s) | Approval agency (year) |
| Liposomes | |||||
| 1 | PEGylated liposomal doxorubicin (MPEG-DSPE, HSPC, cholesterol) | Doxil®, Caelyx® | Janssen | AIDS-related Karposi sarcoma, ovarian cancer, multiple myeloma | FDA (1995, 2005, 2008) EMA (1996) |
| 2 | Non-PEGylated liposomal daunorubicin (DSPC, cholesterol) | DaunoXome® | Galen | Advanced AIDS-related Kaposi’s sarcoma | FDA (1996) |
| 3 | Non-PEGylated liposomal cytarabine (DOPC, DPPG, cholesterol, triolein) | DepoCyt® | DepoTech Corporation | Intrathecal treatment of lymphomatous meningitis | FDA (1999) |
| 4 | Non-PEGylated liposome doxorubicin (PC, cholesterol) | Myocet® | Teva B.V. | Metastatic breast cancer | EMA (2000) |
| 5 | Non-PEGylated liposome paclitaxel | Lipusu® | Luye Pgarna | Breast cancer, NSCLC, lung squamous cell carcinoma | NPMA, P.R. China (2003) |
| 6 | Non-PEGylated liposomal mifamurtide (POPC, OOPS) | Mepact® | Takeda France SAS | Non-metastatic osteosarcoma | EMA (2009) |
| 7 | Non-PEGylated liposomal vincristine (SPH, cholesterol) | Marqibo® | Talon Therapeutics | Philadelphia chromosome-negative acute lymphoblastic leukemia (tertiary) | FDA (2012) |
| 8 | PEGylated liposome doxorubicin (HSPC, DSPE-PEG, cholesterol) | Lipodox® | Sun Pharmaceutical Industries Ltd. | AIDS-associated Kaposi’s sarcoma, metastatic ovarian cancer, multiple myeloma | FDA (2013) |
| 9 | PEGylated liposomal irinotecan (DSPC, MPEG-2000-DSPE, cholesterol) | Onivyde® | Merrimack | Advanced pancreatic cancer | FDA (2015) |
| 10 | Non-PEGylated liposome cytarabine:daunorubicin (5:1 M ratio) (DSPC, DSPG, cholesterol) | Vyxeos® (CPX-351) | Jazz Pharmaceuticals | Acute myeloid leukemia | FDA (2017) EMA (2018) |
| 11 | PEGylated liposome doxorubicin (MPEG-2000-DSPE, HSPC, cholesterol) | Zolsketil® | Accord Healthcare S.L.U. | AIDS-associated Kaposi’s sarcoma, metastatic breast cancer, advanced ovarian cancer, multiple myeloma | EMA (2022) |
| Nanomicelles | |||||
| 12 | Docetaxel (Polysorbate 80) | Taxotere® | Sanofi-Aventis | Advance/metastasis breast cancer | FDA (1996) |
| 13 | Paclitaxel (NIPAM, VP) | Nanoxel® | Samyang Biopharmaceuticals | Metastasis breast cancer, NSCLC, ovarian cancer | MFDS (2012) |
| 14 | Paclitaxel (N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt, N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt) | Paclical® | Oasmia Pharmaceuticals | Ovarian cancer | RFMPH (2015) |
| 15 | Micelles paclitaxel (N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt, N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt) | Apealea® | Inceptua AB | Ovarian cancer, peritoneal cancer, fallopian tube cancer | EMA (2018, withdrawn in 2024) |
| Protein-bound nanoparticles | |||||
| 16 | Engineered protein combining IL-2 and diphtheria toxin | Ontak® | Eisai | Persistent or recurrent cutaneous T-cell lymphoma | FDA (1999) |
| 17 | Human albumin-bound paclitaxel NP | Abraxane® (ABI-007) | Celgene | Metastatic breast cancer, NSCLC, metastatic pancreatic cancer | FDA (2005, 2012, 2013) EMA (2008) |
| 18 | Antibody-drug conjugate (trastuzumab, DM1) | Kadcyla® | Roche Registration GmbH | Early breast cancer, metastatic breast cancer | FDA (2013) EMA (2013) |
| 19 | Human albumin-bound paclitaxel NP | Pazenir® | Ratiopharm GmbH | Metastatic breast cancer, NSCLC | EMA (2019) |
| Polymer nanoparticles: synthetic polymer particles | |||||
| 20 | Polymer-protein conjugate PEGylated L-asparaginase (MPEG) | Oncaspar® | Enzon Pharmaceuticals | ALL and hypersensitivity to asparaginase | FDA (1994, 2006) |
| 21 | Leuprolide acetate and polymer (PLGH or PLG) | Eligard® | Tolmar | Advanced prostate cancer | FDA (2002) |
| 22 | PEG-PLA polymeric micelle paclitaxel | Genexol-PM®, Cynviloq® | Samyang Biopharmaceuticals | Metastasis breast cancer, NSCLC, ovarian cancer | MFDS (2007) |
| 23 | Nanodispersion of a taxane derivative; PICN | Bevetex® | Sun Pharma Advanced Research Company Limited | Metastatic breast cancer | India (N/A) |
Lipid-based nanomaterials are nanoparticles whose structures are composed of lipids with good encapsulation potential, biocompatibility, and simplicity of preparation. They can be classified into two main types [Figure 1B and C]. First, lamellar lipid nanomaterials include liposomes, lipid nanoparticles (LNPs), lipid nanoemulsions (LNEs) or nanomicelles, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid polymer hybrid nanoparticles (LPHNPs)[60]. Second, non-lamellar lipid nanoparticles include nanostructured liquid crystalline particles such as cubosomes and hexosomes[60-64]. The compositions of lipid-based nanomaterials include cholesterol, phospholipids, polymers, and oils to form the structure of lipid-based nanomaterials; helper lipids and PEGylated lipids to enable long circulation inside the body and endosomal escape; and emulsifiers functioning as surfactants. Molecular structures of the lipid-based nanomaterials’ compositions and their limitations are shown in Figure 2 and Table 2. Nanoprecipitation, nonsolvent emulsification, thin film hydration, single/double emulsification, microfluidic mixing, and supercritical fluid techniques are typical synthesis methods [Figure 1D][61].
Figure 2. Molecular structures of common components used in lipid-based nanomedicines for cancer drug research. Group (A) representative lipid-based nanomaterials for cancer drug research include liposomes, LNPs, and nanomicelles (from left to right); group (B) cholesterol; group (C) phospholipids such as HSPC, DSPC, POPC, DOPC, DOPS, DPPG, DSPG, sphingomyelin, and triolein; group (D) ionizable lipids such as ALC-0315 and SM-102; group (E) PEGylated lipids such as MPEG-2000-DSPE, PEG-DMG, and ALC-0159; group (F) oils such as triglyceride, N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt, and N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt; group (G) emulsifiers such as Tween 80; and group (H) polymers such as NIPAM, polyethylene glycol monomethyl ether, poly (DL-lactide-co-glycolide), and poly (DL-lactide). (A) is created by www.Biorender.com, and all chemical structures are generated by ChemDraw Software. LNPs: Lipid nanoparticles; HSPC: fully hydrogenated soy phosphatidylcholine; DSPC: 1,2-distearoyl-sn-glycero-3-phosphocholine or distearoylphosphatidylcholine; POPC: palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; DOPC: 1,2-dioleoyl-sn-glycero-3-phosphocholine; DOPS: 1,2-dioleoyl-sn-glycero-3-phospho-l-serine; DPPG: 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol; DSPG: 1,2-distearoyl-sn-glycero-3-phospho-(1’-rac-glycerol); ALC-0315: (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate); SM-102: (heptadecan-9-yl8-((2-hydroxyethyl)[6-oxo-6(undecyloxy)hexyl]amino)octanoate); PEG: polyethylene glycol; MPEG-2000-DSPE: N-(carbonyl-methoxypolyethyleneglycol-2000)-1,2-distearoly-sn-glycero-3-hosphoethanolamine; PEG-DMG: 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol; ALC-0159: 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide; NIPAM: N-isopropyl acrylamide.
| Types | Compositions | Advantages | Limitations | Status |
| Lamellar lipid nanomaterials | ||||
| Liposomes | Phospholipids (e.g., PC, PS, PE, PG) and cholesterol | Simplicity of preparation Enhanced solubility Biocompatibility Biodegradability Non-immunogenicity Low toxicity | Drug leakage Short half‑life Low reproducibility Possible oxidation and hydrolysis | Commercial products and under clinical trials |
| LNPs | Phospholipids, cholesterol, helper lipids (e.g., DSPC, DPPC, DOPE) and PEGylated lipids (e.g., ALC-0159, DMG-PEG2000, DSPE-PEG2000) | High drug loading Long half-life Biocompatibility Biodegradability Non-immunogenicity Low toxicity | High cost Require specific storage conditions | Preclinical studies |
| LNEs or nanomicelles | Oils (e.g., triglycerides, vegetable oil) and surfactants (e.g., Tween 80) | Self-assembly High reproducibility High penetration to biological membranes | Cytotoxicity due to surfactant Possibility of phase separation | Commercial products and under clinical trials |
| SLNs | Solid lipids (triglycerides, fatty acids, waxes) and emulsifiers, surfactants or polymers | High stability Biocompatibility Free-organic solvents (green synthesis) Reproducibility Ease of scale-up process | Moderate encapsulation efficiency Crystallization Polymorphic transitions High drug expulsion Short shelf-life | Preclinical studies |
| NLCs | Solid lipids, liquid lipids (e.g., glyceryl tricaprylate, ethyl oleate, isopropyl myristate, and glyceryl dioleate) and emulsifiers | Increasing drug loading Low drug expulsion Improving permeability Increasing half-life | High operating tempurature Moderate drug loading Low stability | Preclinical studies |
| LPHNPs | Lipids and polymer (PCL, PLGA, PLA, PbAE, and chitosan) | Flexibility for surface modification High stability Long half-life Control released profile | High cost Difficult to scale up | Preclinical studies |
| Non-lamellar lipid nanoparticles | ||||
| Hexosomes (2D structure), cubosomes (3D structure) | Amphiphilic lipids (monoolein, diolein, phytantriol, phospholipids) and polymeric stabilizer | Highly curved membrane High surface area High loading efficiency (peptides and protein-based drugs) | Early stage of development | Preclinical studies |
Besides good biocompatibility, lipid-based nanomedicines and their derivatives have shown promising results in addressing issues related to immunogenicity[60,69]. The flexibility of the cargo structure allows easy modifications to achieve desired properties. Surface functionalization, such as PEGylation and decoration with targeting ligands, including nucleic acid, peptides, aptamers, and antibodies, is one of the promising strategies to make lipid-based nanomaterials a powerful weapon against cancer drug resistance[27,71-75]. Furthermore, preparation methods, ingredient types and ratios, combination of biocompatible polymers, biomimetic engineering techniques, functional cancer cell-membranes integration, and physicochemical or biochemical trigger mechanisms are all utilized to design advanced lipid-based nanomaterials[70,76]. Combining these modification techniques can adjust lipid structural packing, characteristics, composition at the atomic level, morphology, encapsulation efficiency, biocompatibility, and delivery profile of lipid-based nanomaterials, resulting in improved therapeutic outcomes[50,77]. Following this, researchers and scientists are intensively studying multifunctional lipid-based nanomaterials mainly for the treatment of different cancer types.
Generally, delivering lipid-based nanomedicines to tumor sites is primarily achieved through passive targeting via the enhanced permeability and retention effect (EPR), which preferentially allows them to accumulate in tumors. Notably, nanocarriers can enter cells through three main routes: passive targeting, active targeting, and stimulus-sensitive structures. Firstly, passive targeting occurs when lipid-based nanomaterials penetrate the tumor cellular membranes based on their inherent physicochemical properties. Secondly, active targeting involves modifying the nanocarrier structures with specific moieties that selectively recognize and bind to tumor cells. Lastly, stimulus-sensitive structures regulate the delivery profile of anticancer drugs by responding to external or internal triggers such as pH, temperature, magnetic field, ray, ultrasound, and so on[76,78,79].
Through internalization mechanisms and the customizations of lipid-based nanomaterials, anticancer agents with lipid-based nanomaterials are showing promise in overcoming drug resistance due to their small size, enabling tissue penetration and deep accumulation in tumor tissues, specific targeting, extension of drug circulation in the body, the ability to contain agents with different anticancer mechanisms in one carrier, inhibition of reversible modifications, and alteration of the TME [Figure 3]. Moreover, lipid-based nanomaterials are also capable of co-administration with other treatments to improve therapeutic outcomes and have gained interest as a strategy to cope with drug resistance. Providing a valuable platform for cancer treatment, lipid-based nanomaterials offer material flexibility of their own[60,61].
Figure 3. Illustration of the tactics employed in combatting drug-resistant cancer through the utilization of lipid-based nanomaterials. (A) remodeling of TME; (B) efflux pump inhibition; (C) knockdown or downregulation of anti-apoptotic protein expression pathway; (D) knockdown gene; (E) enhanced drug accumulation; (F) specific targeted drug delivery; and (G) co-delivery systems. Created by www.BioRender.com. TME: Tumor microenvironment.
In this review, the lipid-based nanocarriers including liposomes, LNPs, and nanomicelles are discussed due to their approved and long-standing usage in anticancer nanomedicines. The recent advances to overcome cancer drug resistance using lipid-based nanomedicines and related strategies are summarized. However, the mechanisms of cytotoxic agents are not discussed in this review.
LIPID-BASED NANOMATERIALS FOR CANCER RESISTANCE
Liposomes
Liposomes, classical nanocarriers based on lipid materials, were initially identified in 1965 by Bangham et al.[80]. Structurally, they are spontaneously self-assembling small sphere artificial closed vesicles with sizes varying from 20 to 1,000 nm[36,60,81]. Typical components of liposomes include phospholipids, such as phosphatidylcholines (PC), phosphatidylethanolamines (PE), phosphatidylglycerols (PG), and phosphatidylserines (PS), along with stabilizers such as cholesterol[60]. Nowadays, several nano-delivery systems have been incorporated into clinically used medicines for cancer treatment, including lipid-based nanoparticles, protein-bound nanoparticles, and polymer nanoparticles [Table 1]. Of those, liposomes are particularly promising platforms because of their loading capacity with different hydrophilicity, their superior membrane fusion abilities, and their ease of modifiable properties. In addition, the cell membrane-like structure and components enable liposomes to deliver drugs into cells through membrane fusion and endocytosis, thereby improving the accumulation of drugs in the cytoplasm[78].
Various techniques, including PEGylation and specific ligand attachment, have been employed to enhance the stability and selectivity of liposomes in vivo, thus reducing the occurrence of drug resistance[36,60,73,81]. To increase the accumulation in tumor cells and enhance therapeutic outcomes, liposomes are decorated with surface-attached ligands designed to recognize the specific receptors overexpressed on the surface of various drug-resistant tumor cells. For instance, folate ligands target folate receptor[82-84], transferrin ligands target transferrin receptor[85,86], epidermal growth factor (EGF) protein[87], epidermal growth factor receptor (EGFR) antibody[88], and cetuximab[89,90] target EGFR, and prostate-specific peptide[91] and prostate-specific antigen gene[92] target prostate-specific membrane antigen (PSMA). Additionally, single-stranded DNA aptamer[93] targets forkhead box M1 (FOXM1), biotin[94-97] and fructose[96] target biotin receptor, and humanized anti-human epidermal growth factor receptor 2 (HER2) antibody[98], engineered peptide[99], and bispecific antibody[100] target HER2 receptor. Liposomes can also be designed for controlled release drug delivery to combat cancer drug resistance when exposed to physicochemical or biochemical stimuli, e.g., changes in pH[82,101,102], specific enzymes[103,104], ultrasound[105,106], and so on. Upon exposure to these stimuli, liposomes undergo phase transition, increase membrane permeability, and release loaded active pharmaceutical ingredients at target sites.
In recent years, liposomes have shown their great potential as a delivery tool for combating cancer resistance, because they play a significant role not only in monotherapy by boosting cellular uptake and drug accumulation[107], but also in combination therapy involving multi-treatments through their co-delivery abilities[30,103,108-116]. For example, the furoxans-gemcitabine co-loaded liposome modified with targeted ligands can target the glioblastoma multiforme (GBM) tumor and synergize the radiotherapy (RT) efficacy. Sun et al. developed a reduction-sensitive NO donor conjugate of furoxans-gemcitabine (a RAD51 inhibitor) to serve as a radio-sensitizer for overcoming RT resistance [Figure 4A][112]. The presence of transmembrane efflux pumps is a pivotal challenge for the chemotherapy treatment of multidrug-resistant (MDR) cancers. Previous studies have paid much attention to both monotherapy[117,118] and combination therapy of chemotherapy and transporter inhibitors[103] or siRNA[102,109,119]. As the monotherapy, Bai et al. developed pemetrexed-loaded D-alpha tocopheryl PEG1000 succinate liposome as a highly appealing strategy to overcome MDR mediated by ABCC5, greatly improving the therapeutic efficacy of pemetrexed in breast cancer[117]. A lipidation strategy using phospholipid-conjugation of porphyrin, a photosensitizing drug used in photodynamic treatment, to create benzoporphyrin derivatives has been very informative in evading both P-glycoprotein (P-gp) and ABCG2-mediated transporter in photodynamic treatment-resistant breast cancer. In this study, the authors not only demonstrated the utility of drug-lipid conjugation, but also showed the potential of the lipid material itself to overcome cancer resistance[118]. When it comes to combination therapy, Saw et al. proposed liposomes conjugated with an extra-domain B-specific aptide to simultaneously deliver MDR1 siRNA and DOX to drug-resistant breast tumors. The silencing of MDR-1 increased the intracellular retention of DOX, leading to appreciable tumor growth inhibition in DOX-resistant MCF7/ADR orthotropic model[119]. Furthermore, a TPGS-coated cationic liposome decorated with Bcl-2 siRNA-corona was studied for loading DOX in hepatocellular carcinoma (HCC) for MDR-dual suppression of drug resistance. The system significantly contributed to the inhibition of P-gp efflux and internalization of DOX, thus increasing the in vivo antitumor efficacy[109]. Similarly, an MDR1-siRNA and DOX co-loaded multifunctional liposome with an antibody-conjugated pH-sensitive system was successfully designed to fight P-gp-related MDR by downregulation of P-gp expression and improving DOX antitumor efficiency[102]. Conversely, liposome decorated with PEG and EMC peptide was employed to co-encapsulate DOX and tariquidar, a P-gp inhibitor, to treat triple-negative breast cancer (TNBC). With efficient targeting delivery and a stimuli-responsive system, the liposome has demonstrated superior capability to kill drug-resistant TNBC[103].
Figure 4. Modulation of liposomal delivery system for overcoming cancer drug resistance. (A) Bioluminescence imaging of brain tissues was conducted at specific time intervals. Kaplan–Meier survival curves were complemented to show the treatment outcomes in mouse models. This figure is quoted with permission from Sun et al.[112]; (B) Illustration of how ginsenosides Rg3-PTX-LPs reversed cancer drug resistance by remodeling TME and downregulating the expression of P-gp and reduce the efflux of PTX from the cell. This figure is quoted with permission from Zhu et al.[114]; and (C) Illustration depicting how PFH@LSLP facilitated synergistic antitumor therapy by modulating the hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment. This figure is quoted with permission from Wang et al.[113]. RT: Radiotherapy; PFH: perfluorohexane; LSLP: the combination of LFC131 peptides, sorafenib, and PLX3397.
To target the tumor sites, specific ligand modification is a promising tool against drug resistance. Ginsenosides Rg3, containing a hydrophilic domain with two glucosyl groups, can be recognized by glucose transporter-1 (GLUT-1) on tumor cells. Substitution of cholesterol with the ginsenosides Rg3, a unique Rg3-based liposome loaded with paclitaxel (PTX), was formulated to target cancer cells and remodel the TME. Rg3 showed great potential to reverse drug resistance not only mediated by proteins including P-gp and programmed cell death ligand-1 (PD-L1), but also mediated by immune cells in TME. Hence, Rg3 itself is expected to endow liposomes with potent capability to target tumor sites, prevent PTX efflux, and increase the damage to MDR cancer cells [Figure 4B][114]. Additionally, a perfluorohexane (PFH)-cored liposome modified with LFC131 peptides, a CXCR4 antagonist, can successfully block the SDF-1α/CXCR4 axis through the reversion of the immunosuppressive microenvironment and restoration of the drug sensitivity of tumor cells, thus re-sensitizing the HCC cells to sorafenib [Figure 4C][113].
In summary, various liposome-based approaches are carried out for multifunctional liposomes and combination therapy to enhance tumor targeting and drug accumulation, thus overcoming drug resistance in different types of cancer and improving therapeutic outcomes.
LNPs
The delivery of nucleic acids based on non-viral vectors is a rapidly emerging gene-based therapy that safely reprograms the expression of resistance-associated genes against cancer resistance[120]. From the decades of liposomal development, LNPs have emerged within the pharmaceutical field as potentiate cargoes to carry a wide range of therapeutic agents[69]. LNPs have stemmed from liposomal technology. It has been developed as a four-component formulation that fundamentally contains phospholipids, cholesterol, ionizable lipids, and PEGylated lipids[68]. During the global outbreak of COVID-19, Comirnaty® and Spikevax® are mRNA-encapsulated LNPs for COVID-19 vaccination with FDA approvals in 2020 and 2021, respectively. mRESVIA (mRNA-1345), an mRNA respiratory syncytial virus (RSV) vaccine based on the Spikevax® platform, is also approved by the U.S. FDA in 2024[121,122]. LNPs have rapidly drawn robust attention as an effective tool for transporting and protecting genetic materials into cells[60,123,124]. Interestingly, as a representative milestone, the RNA-LNPs systems of anticancer drugs were examined and administrated to patients with cancer before the massive attention of the RNA-LNPs-based COVID-19 vaccines[125]. Owing to these benefits, the LNPs are further exploited for biomedical applications, particularly for addressing drug resistance issues in cancer therapy. The LNP systems used for delivering anticancer drugs serve to protect and transport genetic materials into cancerous cells, either to erase some reversible modifications or to alter TME[126].
For drug resistance in cancer, numerous studies have demonstrated the potential of LNP composition for targeted gene silencing in combination treatment with chemotherapy nanoformulations[31-33,127-135]. For example, transforming growth factor beta-1 (TGFβ-1) siRNAs encapsulated in LNPs were used as a combination treatment with cabazitaxel (CTX)-conjugated human serum albumin nanoparticles to treat PTX-resistant non-small cell lung cancer (NSCLC) both in vivo and in vitro. The cytoplasmic TGFβ-1 mRNA could be silenced by TGFβ-1 siRNA LNPs, thus reversing acquired drug resistance, restoring PTX sensitivity, and synergistically improving anticancer efficacy in PTX-resistant NSCLC
Figure 5. Modulation of LNP carriers for overcoming cancer drug resistance. (A) The use of combination therapy of CTX-HSA-NPs and TGFβ-1 siRNA LNPs in PTX-resistant NSCLC. This figure is quoted with permission from Tan et al.[32]; (B) The transmission electron microscopy (TEM) and scanning electron microscopy (SEM) images of CTX-HSA-NPs at ratios 6:1, 8:1, and 10:1. This figure is quoted with permission from Tan et al.[32]; (C) LNP-miRs enhanced the efficacy of MAPKi therapy in xenograft melanoma models. The percentage of tumor reduction was determined relative to the initial volumes in mice injected with A375 or M14 from the groups treated with LNP-Scr + MAPKi or LNP-miRs + MAPKi. This figure is quoted with permission from Fattore et al.[128]; (D) A versatile lipid-based nanoplatform for precise co-delivery of sorafenib and Midkine siRNA to hepatic cancer cells. This figure is quoted with permission from Younis et al.[33]; and (E) Overview of mitigating anti-PD-1 resistance through STING-LNP. This figure is quoted with permission from Nakamura et al.[134].
In addition, there is a study about size-controlled LNPs incorporating a highly-selective targeting peptide, a pH-sensitive lipid, and a diversity of phospholipids for selective co-administration of sorafenib and siRNA against the Midkine gene in sorafenib-resistant HCC mice model [Figure 5D]. Results demonstrated that the LNPs showed high tumor accumulation and tissue penetration, and specific gene silencing of Midkine both in vitro and in vivo[33,129]. Another study also showed the potential of targeted LNPs for CRISPR-Cas9 genome editing in two aggressive cancer cell lines. Their LNPs improved the gene editing efficiency of Cas9. Following single local intracerebral administration of this targeted LNPs, Cas9 mRNA and
Furthermore, the pH-sensitive LNPs loaded with stimulators of interferon gene (STING) agonists and anti-PD-1 were reported to circumvent the anti-PD-1 resistance in melanoma lung metastasis mouse model. The developed LNPs can protect STING agonists from predegradation and block the PD-1 on NK cells at tumor sites. After entering the cytoplasm, the agonist would stimulate NK cell activation and efficiently induce a synergistic antitumor activity [Figure 5E][134].
Collectively, the excellent properties of LNPs for protecting and delivering genetic materials into cells endow them with potent capabilities against drug-resistant tumors. They provide efficient platforms for regulating the oncogene expression and improving the efficacy of gene therapy. Importantly, further in-depth explosion is necessary for the safe and efficient clinical application of LNP-based nanomedicines.
Nanomicelles
Nanomicelles are nanosized colloidal constructs formed by self-assembling of amphiphilic molecules stabilized by emulsifiers with a hydrophobic core and hydrophilic shell in aqueous media. They are usually spherical in shape with a diameter size from 5 to 100 nm. Various oils used as lipid phase in nanomicelles include vegetable oils, glycerides, long-chain unsaturated fatty acids, medium-chain triglycerides, and polyalcohol esters of medium-chain fatty acids. Indeed, different types of emulsifiers, such as phospholipids (e.g., soy lecithin), proteins (e.g., caseinate), surfactants (e.g., Tween 80, sodium dodecyl sulfate), polysaccharides (e.g., modified starch), or polymers [e.g., poly(vinyl alcohol), PEG], are applied to stabilize the interfacial surface to avoid aggregation by steric effects or electrostatic interactions, hydration, and thermal fluctuations[67]. Nanomicelles can encapsulate various drug molecules through their delivery systems, such as water-in-oil emulsion (regular micelles), oil-in-water emulsion (reverse micelles), or water-in-oil-in-water emulsion prepared through various techniques, thus increasing the solubility of the drug[136].
Nanomicelles can also be modified with specific ligands or triggered by selective stimuli to improve efficacy and drug release profile[104,137,138]. Since 1996, Taxotere®, a docetaxel nanomicelle, is the only FDA-approved nanomicelle formulation launched on the market for locally advanced or metastatic breast cancer after the ineffectiveness of previous chemotherapy [Table 1]. Nowadays, the gradually increasing drug resistance in various types of tumors provides opportunities for nanomicelles to be developed and evaluated in preclinical trials.
Targeted nanomicellar systems were developed to challenge drug resistance in cancer. A PEGylated lipid-core nanomicelle decorated with Arg-Gly-Asp peptides (RGD) peptides was engineered to enhance the active targeting of docetaxel (DTX) on TNBC. This delivery system showed high drug loading, long drug retention time in the circulation system, sustained release profile, and reduced side effects of DTX after intravenous administration in MDA-MB-231 xenograft mice model [Figure 6A][138]. Based on lipid-nanomicelles, many combination therapies for cancer resistance have been widely developed[104,138]. PEGylated nanomicelles consisting of DSPE-PEG2000 were developed to co-encapsulate PTX and Zos bound with a redox-responsive disulfide linkage. The results suggested that nanomicelles improved intracellular drug accumulation in tumor cells and simultaneously inhibited the MDR tumor growth without systemic toxicity[104].
Figure 6. Modulation of lipid nanomicellar delivery system for overcoming cancer drug resistance. (A) In vitro cellular uptake of RGD-DTX-M by MDA-MB-231 cells. **P < 0.01; ****P < 0.0001. This figure is quoted with permission from Chen et al.[138]; (B) Diagram depicting the biodegradable pH-sensitive micellar systems and elucidation of the in vivo tumor targeting and mechanisms underlying the anti-MDR effect. This figure is quoted with permission from Gao et al.[137]; (C) The alteration in zeta potential observed in various formulations of pH-responsive PHIS-PEG2000 and DSPE-PEG2000 hybrid micelles. This figure is quoted with permission from Gao et al.[137]; and (D) Schematic representation of multifaced lipid and micelle formulation employed in HCC. This figure is quoted with permission from Wu et al.[116]. RGD: (Arg-Gly-Asp) peptides; DTX: docetaxel; MDA-MB-231: human triple negative breast cancer cell line; MDR: multidrug-resistant; HCC: hepatocellular carcinoma.
Similar to liposomes and LNPs, nanomicelles can also be modified with specific receptors or designed to response to stimuli to enhance the therapeutic outcomes[137]. For example, as a targeted pH-sensitive nanomicellar system for MDR breast cancer, the DOX-loaded nanomicelle conjugated with PEGylated and transferrin receptor ligand-modified lipid can significantly enhance the cellular uptake and the capacity to damage cancer cells [Figure 6B and C][137].
Moreover, the combination of lipid nanosystems was also introduced to treat resistant cancer. A multifunctional DOX-loaded nanomicelle, alongside capsaicin and telmisartan co-loaded liposome, was developed to prevent drug resistance development in tumor cells. This combinational therapy can inhibit the cross-talk between tumor cells and cancer-associated fibroblasts in TME, thus reducing the deposition of extracellular matrix and reversing the epithelial-mesenchymal transition (EMT) of tumor cells. The synergistic anti-HCC efficacy with good biocompatibility and safety makes this combinational therapy a potential tool for combating cancer resistance [Figure 6D][116]. These findings provide crucial insights for further strategies in clinical interventions against cancer drug resistance.
LIPID-BASED NANOMEDICINES FOR DRUG-RESISTANT CANCER THERAPY IN CLINICAL TRIALS
During the last decade, lipid-based nanomedicines have been examined in numerous clinical trials to investigate new standard regimens as monotherapy and combination therapy with other approaches for drug-resistant cancer. Table 3 shows the clinical trials of lipid-based nanomedicines to cope with cancer drug resistance from 2017 to the present.
Lipid-based nanomedicines for the development of drug-resistant cancer treatments, selected from phase I, II, and III clinical trials
| ClinicalTrials.gov identifiers | Sponsor | Medication | Study title |
| Phase I | |||
| NCT04718376 (phase I, terminated, 2024) | CSPC ZhongQi Pharmaceutical Technology Co., Ltd. | 1. Mitoxantrone hydrochloride liposome | A multicenter, open-label, single-arm, phase Ib study to evaluate the safety and efficacy of mitoxantrone hydrochloride liposome injection in subjects with platinum-resistant or platinum-refractory relapsed ovarian cancer |
| NCT05483933 (phase I, active, not recruiting, 2024) | Shattuck Labs, Inc. | 1. PLD + SL-172154 (SIRPα-Fc-CD40L) 2. Mirvetuximab + SL-172154 | An open-label, phase 1b study of SL-172154 (SIRPα-Fc-CD40L) administered with either pegylated liposomal doxorubicin or mirvetuximab soravtansine in subjects with platinum-resistant ovarian cancers |
| NCT02751918 (phase I, completed, 2019) | Bayer | 1. Anetumab ravtansine (BAY94-9343) + PLD | An open-label phase Ib dose escalation study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and maximum tolerated dose of anetumab ravtansine in combination with pegylated liposomal doxorubicin 30 mg/m2 given every 3 weeks in subjects with mesothelin-expressing platinum-resistant recurrent ovarian, fallopian tube, or primary peritoneal cancer |
| NCT03591276 (phase I, unknown, 2020) | Shaare Zedek Medical Center | 1. Pembrolizumab + PLD | A phase 1b study of combination chemoimmunotherapy with pegylated liposomal doxorubicin (Doxil/Caelyx) and pembrolizumab (Keytruda) in metastatic endocrine-resistant breast cancer |
| NCT05261490 (phase I, terminated, 2024) | Pfizer | 1. Maplirpacept (PF-07901801) + PLD | A phase I/II study of TTI-622 in combination with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer |
| NCT03639246 (phase I, completed, 2023) | Aravive, Inc. | 1. AVB-S6-500 + PLD 2. AVB-S6-500 + PTX 3. Placebo + PLD 4. Placebo + PTX | A phase 1b/2 randomized, controlled study of AVB-S6-500 in combination with PLD or Pac in patients with platinum-resistant recurrent ovarian cancer |
| NCT03596281 (phase I, active, not recruiting, 2023) | Gustave Roussy, Cancer Campus, Grand Paris | 1. Pembrolizumab + PLD 2. Pembrolizumab + bevacizumab | An open-label phase 1 of pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer |
| NCT03480750 (phase I, completed, 2020) | National Cheng-Kung University Hospital | 1. Trientine + PLD + carboplatin | Phase I trial of copper chelator in conjunction with pegylated liposomal doxorubicin and carboplatin in patients with platinum-resistant/refractory epithelial ovarian cancer, tubal cancer, and primary peritoneal cancer |
| NCT01035658 (phase I, terminated, 2021) | SCRI Development Innovations, LLC | 1. Pazopanib + Doxil® | A phase I/II study of the combination of pazopanib and liposomal doxorubicin (Doxil) in patients with advanced relapsed platinum-sensitive or platinum-resistant ovarian, fallopian tube, or primary peritoneal adenocarcinoma |
| NCT02431559 (phase I, completed, 2022) | Ludwig Institute for Cancer Research | 1. Durvalumab + PLD | Phase 1/2 study of chemoimmunotherapy with toll-like receptor 8 agonist motolimod (VTX-2337) + anti-PD-L1 antibody MEDI4736 in subjects with recurrent, platinum-resistant ovarian cancer for whom pegylated liposomal doxorubicin is indicated |
| NCT04092270 (phase I, recruiting, 2024) | NCI | 1. peposertib + PLD | A phase I/Ib dose escalation study of PLD with peposertib (M3814) in platinum-resistant or ineligible ovarian and related cancers with planned expansions in HGSOC and LGSOC |
| NCT05271318 (phase I, recruiting, 2024) | TILT Biotherapeutics Ltd. | 1. TILT-123 + pembrolizumab 2. TILT-123 + pembrolizumab + PLD | A two-part, phase I/Ib, open-label, dose-escalation trial of tumor necrosis factor alpha and interleukin-2 coding oncolytic adenovirus (TILT-123) in combination with pembrolizumab (phase i part) and pembrolizumab and pegylated liposomal doxorubicin (phase ib part) in patients with platinum-resistant or refractory ovarian cancer |
| Phase II | |||
| NCT00913835 (phase II, completed, 2019) | Eli Lilly and Company | 1. Olaratumab + PLD 2. PLD or olaratumab monotherapy | Randomized phase 2 trial investigating liposomal doxorubicin with or without anti-PDGFRα monoclonal antibody IMC-3G3 in patients with platinum-refractory or platinum-resistant advanced ovarian cancer |
| NCT03161132 (phase II, completed, 2023) | Grupo Español de Investigación en Cáncer de Ovario | 1. Olaparib 2. PLD | Multicentric single-arm phase II clinical trial to evaluate the safety and efficacy of the combination of olaparib and PLD for platinum-resistant ovarian primary peritoneal carcinoma, and fallopian tube cancer patients |
| NCT03335241 (phase II, unknown status, 2017) | Sun Yat-sen University | 1. Fludarabine + PLD 2. PLD | An open-label, randomized phase II study of fludarabine with pegylated liposomal doxorubicin vs. pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory ovarian cancer |
| NCT03509246 (phase II, unknown status, 2020) | Seoul National University Hospital | 1. PLD + bortezomib | A phase II trial to evaluate the efficacy of bortezomib and pegylated liposomal doxorubicin in patients with BRCA wild-type platinum-resistant recurrent ovarian cancer |
| NCT04753216 (phase II, completed, 2023) | Northwestern University | 1. Bevacizumab + irinotecan liposome | A phase II trial of irinotecan liposome and bevacizumab in women with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer |
| NCT03071926 (phase II, unknown status, 2022) | Fudan University | 1. PLD | Efficacy and safety of metronomic pegylated liposomal doxorubicin in patients with primary endocrine-resistant advanced breast cancer |
| NCT02865811 (phase II, completed, 2022) | Dana-Farber Cancer Institute | 1. Pembrolizumab + PLD | A phase II study of pembrolizumab combined with PLD for recurrent platinum-resistant ovarian, fallopian tube, or peritoneal cancer |
| NCT03591276 (phase 1b, unknown status, 2020) | Shaare Zedek Medical Center | 1. Pembrolizumab + PLD | A phase 1b study of combination chemoimmunotherapy with pegylated liposomal doxorubicin (Doxil/Caelyx) and pembrolizumab (Keytruda) in metastatic endocrine-resistant breast cancer |
| NCT05261490 (phase II, terminated, 2024) | Pfizer | 1. Maplirpacept (PF-07901801) + PLD | A phase I/II study of TTI-622 in combination with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer |
| NCT01991210 (phase II, terminated, 2017) | Genentech, Inc. | 1. DNIB0600A 2. PLD | A randomized, open-label, multicenter, phase II trial evaluating the safety and activity of DNIB0600A compared to pegylated liposomal doxorubicin administered intravenously to patients with platinum-resistant ovarian cancer |
| NCT05467670 (phase II, recruiting, 2023) | Haider Mahdi | 1. ALX148 + PLD + pembrolizumab | Safety and efficacy of anti-CD47, ALX148 in combination with liposomal doxorubicin and pembrolizumab in patients with recurrent platinum-resistant ovarian cancer: phase II study |
| NCT03480750 (phase II, completed, 2020) | National Cheng-Kung University Hospital | 1. Trientine + PLD + carboplatin | Phase I trial of copper chelator in conjunction with pegylated liposomal doxorubicin and carboplatin in patients with platinum-resistant/refractory epithelial ovarian cancer, tubal cancer, and primary peritoneal cancer |
| NCT01035658 (phase II, terminated, 2021) | SCRI Development Innovations, LLC | 1. Pazopanib + Doxil® | A phase I/II study of the combination of pazopanib and liposomal doxorubicin (Doxil®) in patients with advanced relapsed platinum-sensitive or platinum-resistant ovarian, fallopian tube, or primary peritoneal adenocarcinoma |
| NCT02431559 (phase II, completed, 2022) | Ludwig Institute for Cancer Research | 1. Durvalumab + PLD | A phase 1/2 study of chemoimmunotherapy with toll-like receptor 8 agonist motolimod (VTX-2337) + anti-PD-L1 antibody MEDI4736 in subjects with recurrent, platinum-resistant ovarian cancer, for whom pegylated liposomal doxorubicin is indicated |
| NCT03268382 (phase II, completed, 2024) | Aprea Therapeutics | 1. APR-246 + PLD | PiSARRO-R: p53 suppressor activation in platinum-resistant high-grade serous ovarian cancer, a phase II study of systemic pegylated liposomal doxorubicin chemotherapy with APR-246 |
| NCT06014528 (phase II, recruiting, 2023) | InxMed (Shanghai) Co., Ltd. | 1. IN10018 + PLD 2. Placebo + PLD | A multicenter, randomized, double-blind, phase II clinical study of IN10018 in combination with PLD vs. placebo in combination with PLD for the treatment of platinum-resistant recurrent ovarian cancer |
| NCT03804866 (phase II, completed, 2019) | AGC Biologics S.p.A. | 1. NGR-hTNF + PLD 2. PLD | NGR018: randomized phase II study of NGR-hTNF plus an anthracycline vs. an anthracycline alone in platinum-resistant ovarian cancer |
| NCT01358071 (phase II, completed, 2018) | AGC Biologics S.p.A. | 1. NGR-hTNF + PLD 2. PLD | NGR018: randomized phase II study of NGR-hTNF plus an anthracycline vs. an anthracycline alone in platinum-resistant ovarian cancer |
| NCT02839707 (phase II, active, not recruiting, 2023) | NCI | 1. PLD + atezolizumab 2. PLD + bevacizumab + atezolizumab 3. PLD + bevacizumab | A randomized, phase II/III study of pegylated liposomal doxorubicin and CTEP-supplied atezolizumab vs. pegylated liposomal doxorubicin, CTEP-supplied bevacizumab and CTEP-supplied atezolizumab vs. pegylated liposomal doxorubicin and CTEP-supplied bevacizumab in platinum-resistant ovarian cancer |
| NCT01593488 (phase II, active, not recruiting, 2023) | NCI, Naples | 1. Liposomal cytarabine | Multicentered phase II study evaluating the activity and toxicity of liposomal cytarabine in the treatment of children and adolescents with acute lymphoblastic leukemia with resistant or relapsed central nervous system involvement |
| NCT00466960 (phase II, completed, 2017) | University of Washington | 1. Sargramostim + paclitaxel albumin-stabilized nanoparticle formulation | A phase II trial of GM-CSF with weekly protein-bound paclitaxel (Abraxane™) as chemoimmunotherapy for platinum-refractory/resistant epithelial ovarian, primary peritoneal, and fallopian tube cancer |
| NCT00499252 (phase II, completed, 2022) | Gynecologic Oncology Group | 1. Paclitaxel albumin-stabilized nanoparticle formulation | A phase II evaluation of Abraxane® in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer |
| NCT03531827 (phase II, terminated, 2022) | NCI | 1. Enzalutamide + CRLX101 | A single-arm phase II study combining CRLX101, a nanoparticle camptothecin, with enzalutamide in patients with progressive metastatic castration-resistant prostate cancer following prior enzalutamide treatment |
| Phase III | |||
| NCT02580058 (phase III, completed, 2023) | Pfizer | 1. Avelumab 2. Avelumab + PLD | A phase 3, multicenter, randomized, open-label study of avelumab (MSB0010718C) alone or in combination with pegylated liposomal doxorubicin vs. pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory ovarian cancer |
| NCT02421588 (phase III, completed, 2020) | PharmaMar | 1. Lurbinectedin (PM01183) 2. PLD + topotecan | Phase III randomized clinical trial of lurbinectedin (PM01183) vs. pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer (CORAIL trial) |
| NCT01170650 (phase III, terminated, 2021) | Endocyte | 1. EC145 + PLD (Doxil®/Caelyx®) 2. Placebo + PLD (Doxil®/Caelyx®) | A randomized, double-blind phase 3 trial comparing EC145 and pegylated liposomal doxorubicin (PLD/Doxil®/Caelyx®) in combination vs. PLD alone in participants with platinum-resistant ovarian cancer |
| NCT01281254 (phase III, terminated, 2017) | Amgen | 1. AMG386 + PLD 2. Placebo + PLD | A phase 3, randomized, double-blind trial of PLD plus AMG386 or placebo in women with recurrent partially platinum-sensitive or |
| NCT00262990 (phase III, completed, 2020) | Novartis Pharmaceuticals | 1. Patupilone 2. PLD | A randomized, parallel group, open-label, active controlled, multicenter phase III trial of patupilone (EPO906) vs. pegylated liposomal doxorubicin in taxane-/platinum-refractory/resistant patients with recurrent epithelial ovarian, primary fallopian, or primary peritoneal cancer |
| NCT02839707 (phase III, active, not recruiting, 2023) | NCI | 1. PLD + atezolizumab 2. PLD + bevacizumab + atezolizumab 3. PLD + bevacizumab | A randomized, phase II/III study of pegylated liposomal doxorubicin and CTEP-supplied atezolizumab vs. pegylated liposomal doxorubicin, CTEP-supplied bevacizumab and CTEP-supplied atezolizumab vs. pegylated liposomal doxorubicin and CTEP-supplied bevacizumab in platinum-resistant ovarian cancer |
| NCT04729387 (phase III, active, not recruiting, 2024) | Novartis Pharmaceuticals | 1. Alpelisib + olaparib 2. PTX or PLD | EPIK-O: a phase III, multicenter, randomized (1:1), open-label, active-controlled study to assess the efficacy and safety of alpelisib (BYL719) in combination with olaparib as compared to single-agent cytotoxic chemotherapy, in participants with no germline BRCA mutation detected, platinum-resistant or refractory, high-grade serous ovarian cancer |
LIMITATIONS OF LIPID-BASED NANOMEDICINES DEVELOPMENT
Advancements in lipid-based nanomedicines have been driven by innovative drug delivery systems, targeted therapies, and related modern technologies[50,53]. Although lipid-based nanomedicines show promising therapeutic advantages, the preparation method and manufacturing at a large scale with reproducibility are still challenging, especially for complex lipid nanocarriers[53]. The selection of the synthesis method is crucial to determining their therapeutic applications. Different preparation techniques exhibit different drawbacks, which can affect the properties of both nanocarriers and active pharmaceutical ingredients[61]. For example, the degradation of drugs during the manufacturing process occurs due to the heat and force from high-pressurized homogenization and ultrasonication. Non-uniformity in size, zeta potential, and PDI is also observed due to inconsistent synthesis processes such as variations in temperature, mixing speed, and extrusion force from batch to batch[61]. Numbers of parameters can significantly affect the physicochemical characteristics of nanoparticles. Precise process control of each parameter and condition is necessary to ensure uniformity and minimize the variation among batches[61]. Automated machines, such as microfluidic mixer, can be utilized for this purpose[139]. Sterilization of finished products is of particular concern, especially during testing in clinical trials[140]. Concerns are also raised regarding the toxicity of residual organic solvents in certain preparation methods[141].
Challenges are also presented in the clinical trial process. Pharmacodynamics and pharmacokinetics are influenced by biological environments and remain significant issues for efficacy and safety in both the short-term and long-term outcomes. Specific storage conditions, such as extremely low temperature requirements, contribute to the complexity of logistics and expenses, as well as impacting therapeutic outcomes. The occurrence of chemical degradation, e.g., lipid oxidation and hydrolysis, can affect their shelf life and efficacy. In addition, stringent regulatory requirements for conducting clinical trials and approval processes are complex and costly[50,53,57,142].
PERSPECTIVES
To overcome the challenges, the research direction should focus on developing more stable and scalable lipid-based nanomedicines. Method validation and quality control are crucial but compromise cost-effective manufacturing. Investigating the use of novel ligands for targeted delivery and exploring the potential of combination therapies could provide new insights. Long-term preclinical trials are also important for understanding the pharmacokinetics and pharmacodynamics of these systems.
Robust studies confirm the significant progress of lipid-based nanomaterials in improving drug delivery, synergizing therapeutic effects, and overcoming drug resistance. Lipid-based nanomaterials can unlock the advanced applications of potent anticancer agents derived from various natural substances by delivering the phytochemicals, which are often restricted to their limited solubility, to the targeted organs[143]. Lipid-based nanomaterials enable additional administration routes to increase therapeutic effects and enhance patient compliance, thereby enabling personalized treatment options. Besides investigating novel cytotoxic agents, there is considerable focus on the identification of new indications for existing clinically approved drugs or repurposing them for cancer therapy. Theoretically, repurposed drugs may help shorten the time required for the research and development process and significantly reduce resistance to current therapeutic regimens[61,144]. Utilization of lipid-based nanomaterials will make the repurposed drug more efficient and safe. In the meantime, there is an urgent need for a rapid, high-accuracy tool for lipid-based theranostics to address cancer resistance[145,146]. NanoBodipy, a nitroreductase-responsive dye, was recently invented as a smart optical nanoprobe for non-invasive and real-time tumor-targeted imaging. This innovation can accumulate in tumors via the EPR effect, which is beneficial for tumor resection surgery guidance as a theranostic agent to achieve complete tumor removal, thereby reducing the prevalence of drug resistance in remaining cancerous cells[147].
Artificial intelligence (AI) technology is increasingly playing important roles in areas such as lipid nanotechnology design and cancer drug resistance modeling, by gathering existing data and creating excellent algorithms[148]. EVONANO, an AI platform, has recently been developed as a simulation platform to design nanomedicines according to the optimized treatment parameters for cancer treatment. This in silico model simulates virtual tumor growth and tissue-scale dynamics, integrating machine learning to identify the most effective anticancer nanomedicines[149]. It could save both time and cost in lipid-based nanomaterials development and significantly advance the field of nanomedicine.
To the best of our knowledge, technological advancements and the integration of modern technology have remarkably revolutionized cancer research, diagnosis, therapy, and cancer management. Their applications have the potential to transform the administration of various therapeutic agents, including gene therapy and vaccines, thereby significantly impacting clinical practices. Addressing these issues requires multidisciplinary collaboration, innovative engineering solutions, comprehensive preclinical and clinical studies, and well-rounded development of regulations.
CONCLUSION
The development of cancer drug resistance often limits the effectiveness of treatment regimens and leads to relapse, recurrence, and fatality. The development of lipid-based nanomaterials, stemmed from natural vesicles of human body, presents promising avenues for cancer treatment. These nanomaterials, due to their nano-scale size, biocompatibility, flexibility for surface modification, and production techniques, are currently being investigated for the development of new formulations and modifications of existing anticancer agents to offer viable solutions to combat cancer drug resistance. The progress of nanomedicines based on lipid-based nanomaterials is poised to alleviate global burden and improve human health.
To date, robust studies have shown that lipid-based nanotechnology plays a significant role in overcoming drug resistance in cancer treatment. Integrating various anticancer agents and genetic materials into lipid-based nanomaterials can enhance drug tolerability, reduce drug-induced toxicity, reverse some resistant-related mechanisms, and alter the TME. The superiority of these nanomaterials results in the enhancement and synergy of therapeutic effects of anticancer drugs while reducing the occurrence of cancer drug resistance, ultimately improving sensitivity to traditional drugs and survival rates.
In addition to pharmacogenomics, proteomics, and metabolomics, there is considerable potential for leveraging AI technology in computational modeling, mathematical modeling, and machine learning. These avenues hold promise for developing novel tools to predict disease progression and cancer resistance, thereby advancing personalized medicine. To achieve this ambitious goal, it is imperative to gather and analyze the clinical data of patients suffering from resistant cancer using AI algorithms. Predictive models for the most likely outcomes and progressions of cancer could lead to significant improvement in cancer management. However, the implementation of these new methods in clinical care necessitates extensive studies and time investment. Accelerating the translation of these modern technologies to support cancer treatment requires robust collaborations and networking among researchers, clinicians, hospitals, and industry stakeholders, as well as many relative efforts. Interdisciplinary partnerships play a pivotal role in addressing the complex challenges and harnessing the full potential of lipid-based nanomedicines.
DECLARATIONS
Authors’ contributions
Investigation, writing, revising, and editing of the manuscript: Dechbumroong P
Investigation, writing, and editing of the manuscript: Hu R
Revised the manuscript: Namdee K
Revised and edited the manuscript: Keaswejjareansuk W
Initiated and supervised the research, and revised the manuscript: Liang XJ
Availability of data and materials
Not applicable.
Financial support and sponsorship
This work was supported by OCSC Royal Thai Government-UCAS Scholarship and National Science and Technology Development Agency and the Chinese Academy of Sciences (NSTDA-CAS) Joint Research Program (grant No. P2250326). This work was also supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB36000000), the National Key Research & Development Program of China (grant No. 2021YFA1201000), the National Natural Science Foundation of China (NSFC) key project (grant No. 32030060), NSFC international collaboration key project (grant No. 51861135103). The authors also appreciate the support of “the Chinese Academy of Sciences (CAS-NSTDA) International Partnership Program” (121D11KYSB20210003).
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
REFERENCES
1. American Cancer Society. Cancer Statistics Center. Available from: https://cancerstatisticscenter.cancer.org/module/BmVYeqHT. [Last accessed on 19 Jun 2024].
2. Luque-Bolivar A, Pérez-Mora E, Villegas VE, Rondón-Lagos M. Resistance and overcoming resistance in breast cancer. Breast Cancer 2020;12:211-29.
3. Ji X, Lu Y, Tian H, Meng X, Wei M, Cho WC. Chemoresistance mechanisms of breast cancer and their countermeasures. Biomed Pharmacother 2019;114:108800.
4. MacDonagh L, Gray SG, Breen E, et al. Lung cancer stem cells: the root of resistance. Cancer Lett 2016;372:147-56.
5. Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol 2016;22:6876-89.
6. Nakazawa M, Paller C, Kyprianou N. Mechanisms of therapeutic resistance in prostate cancer. Curr Oncol Rep 2017;19:13.
7. Cai M, Song XL, Li XA, et al. Current therapy and drug resistance in metastatic castration-resistant prostate cancer. Drug Resist Updat 2023;68:100962.
9. Sarmento-Ribeiro AB, Scorilas A, Gonçalves AC, Efferth T, Trougakos IP. The emergence of drug resistance to targeted cancer therapies: clinical evidence. Drug Resist Updat 2019;47:100646.
10. Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers 2014;6:1769-92.
11. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013;13:714-26.
12. Gottesman MM, Robey RW, Ambudkar SV. New mechanisms of multidrug resistance: an introduction to the Cancer Drug Resistance special collection. Cancer Drug Resist 2023;6:590-5.
13. Haider T, Pandey V, Banjare N, Gupta PN, Soni V. Drug resistance in cancer: mechanisms and tackling strategies. Pharmacol Rep 2020;72:1125-51.
17. Zahreddine H, Borden KLB. Mechanisms and insights into drug resistance in cancer. Front Pharmacol 2013;4:28.
18. Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: a current overview. Clin Exp Metastasis 2018;35:309-18.
19. Aleksakhina SN, Kashyap A, Imyanitov EN. Mechanisms of acquired tumor drug resistance. Biochim Biophys Acta Rev Cancer 2019;1872:188310.
20. Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci 2020;21:3233.
21. Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist 2019;2:141-60.
22. Su Z, Dong S, Zhao SC, et al. Novel nanomedicines to overcome cancer multidrug resistance. Drug Resist Updat 2021;58:100777.
23. Anselmo AC, Mitragotri S. Nanoparticles in the clinic: an update. Bioeng Transl Med 2019;4:e10143.
24. Shan X, Gong X, Li J, Wen J, Li Y, Zhang Z. Current approaches of nanomedicines in the market and various stage of clinical translation. Acta Pharm Sin B 2022;12:3028-48.
26. Namiot ED, Sokolov AV, Chubarev VN, Tarasov VV, Schiöth HB. Nanoparticles in clinical trials: analysis of clinical trials, FDA approvals and use for COVID-19 vaccines. Int J Mol Sci 2023;24:787.
27. Ashique S, Garg A, Hussain A, Farid A, Kumar P, Taghizadeh-Hesary F. Nanodelivery systems: an efficient and target-specific approach for drug-resistant cancers. Cancer Med 2023;12:18797-825.
28. Patel KD, Singh RK, Kim HW. Carbon-based nanomaterials as an emerging platform for theranostics. Mater Horiz 2019;6:434-69.
29. Tan C, Hosseini SF, Jafari SM. Cubosomes and hexosomes as novel nanocarriers for bioactive compounds. J Agric Food Chem 2022;70:1423-37.
30. Mendes LP, Sarisozen C, Luther E, Pan J, Torchilin VP. Surface-engineered polyethyleneimine-modified liposomes as novel carrier of siRNA and chemotherapeutics for combination treatment of drug-resistant cancers. Drug Deliv 2019;26:443-58.
31. Quick J, Santos ND, Cheng MHY, et al. Lipid nanoparticles to silence androgen receptor variants for prostate cancer therapy. J Control Release 2022;349:174-83.
32. Tan T, Feng Y, Wang W, et al. Cabazitaxel-loaded human serum albumin nanoparticles combined with TGFβ-1 siRNA lipid nanoparticles for the treatment of paclitaxel-resistant non-small cell lung cancer. Cancer Nano 2023;14:70.
33. Younis MA, Khalil IA, Abd Elwakil MM, Harashima H. A multifunctional lipid-based nanodevice for the highly specific codelivery of sorafenib and midkine siRNA to hepatic cancer cells. Mol Pharm 2019;16:4031-44.
34. Chen Q, Wang Q, Wang Y, et al. Penetrating micelle for reversing immunosuppression and drug resistance in pancreatic cancer treatment. Small 2022;18:e2107712.
35. Joshi U, Filipczak N, Khan MM, Attia SA, Torchilin V. Hypoxia-sensitive micellar nanoparticles for co-delivery of siRNA and chemotherapeutics to overcome multi-drug resistance in tumor cells. Int J Pharm 2020;590:119915.
36. Lasa-Saracibar B, Estella-Hermoso de Mendoza A, Guada M, Dios-Vieitez C, Blanco-Prieto MJ. Lipid nanoparticles for cancer therapy: state of the art and future prospects. Expert Opin Drug Deliv 2012;9:1245-61.
37. Markman JL, Rekechenetskiy A, Holler E, Ljubimova JY. Nanomedicine therapeutic approaches to overcome cancer drug resistance. Adv Drug Deliv Rev 2013;65:1866-79.
38. Majidinia M, Mirza-Aghazadeh-Attari M, Rahimi M, et al. Overcoming multidrug resistance in cancer: recent progress in nanotechnology and new horizons. IUBMB Life 2020;72:855-71.
39. Sonju JJ, Dahal A, Singh SS, Jois SD. Peptide-functionalized liposomes as therapeutic and diagnostic tools for cancer treatment. J Control Release 2021;329:624-44.
40. Ventola CL. Progress in nanomedicine: approved and investigational nanodrugs. P T 2017;42:742-55.
41. Sainz V, Conniot J, Matos AI, et al. Regulatory aspects on nanomedicines. Biochem Biophys Res Commun 2015;468:504-10.
42. Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res 2016;33:2373-87.
43. U.S. Food & Drug Administration. Considerations for drug products that contain nanomaterials. Available from: https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/considerations-drug-products-contain-nanomaterials. [Last accessed on 19 Jun 2024].
44. Jeevanandam J, Barhoum A, Chan YS, Dufresne A, Danquah MK. Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations. Beilstein J Nanotechnol 2018;9:1050-74.
45. DeFrates K, Markiewicz T, Gallo P, et al. Protein polymer-based nanoparticles: fabrication and medical applications. Int J Mol Sci 2018;19:1717.
46. Barenholz Y. Doxil® - the first FDA-approved nano-drug: lessons learned. J Control Release 2012;160:117-34.
47. Choi YH, Han HK. Nanomedicines: current status and future perspectives in aspect of drug delivery and pharmacokinetics. J Pharm Investig 2019;48:43-60.
48. D’Mello SR, Cruz CN, Chen ML, Kapoor M, Lee SL, Tyner KM. The evolving landscape of drug products containing nanomaterials in the United States. Nat Nanotechnol 2017;12:523-9.
49. Banala VT, Mukherjee D, Mahajan S, Singh PK. Chapter 20 - Current status of FDA-approved marketed nano drug products: regulatory considerations. In: Multifunctional Nanocarriers. Elsevier; 2022. pp. 501-21.
50. Farjadian F, Ghasemi A, Gohari O, Roointan A, Karimi M, Hamblin MR. Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportunities. Nanomedicine 2019;14:93-126.
51. National Cancer Institute. Cancer nano-therapies in the clinic and clinical trials. Available from: https://www.cancer.gov/nano/cancer-nanotechnology/current-treatments. [Last accessed on 19 Jun 2024].
53. Rodríguez F, Caruana P, De la Fuente N, et al. Nano-based approved pharmaceuticals for cancer treatment: present and future challenges. Biomolecules 2022;12:784.
54. Halwani AA. Development of pharmaceutical nanomedicines: from the bench to the market. Pharmaceutics 2022;14:106.
55. Fraguas-Sanchez AI, Martin-Sabroso C, Fernandez-Carballido A, Torres-Suarez AI. Chapter 4 - Current status of nanomedicine for breast cancer treatment. In: Targeted Nanomedicine for Breast Cancer Therapy. 2022. pp. 65-110.
56. Fraguas-Sánchez AI, Lozza I, Torres-Suárez AI. Actively targeted nanomedicines in breast cancer: from pre-clinal investigation to clinic. Cancers 2022;14:1198.
57. Crommelin DJA, van Hoogevest P, Storm G. The role of liposomes in clinical nanomedicine development. What now? Now what? J Control Release 2020;318:256-63.
58. Madaan A, Singh P, Awasthi A, et al. Efficiency and mechanism of intracellular paclitaxel delivery by novel nanopolymer-based tumor-targeted delivery system, Nanoxel(TM). Clin Transl Oncol 2013;15:26-32.
59. Sofias AM, Dunne M, Storm G, Allen C. The battle of “nano” paclitaxel. Adv Drug Deliv Rev 2017;122:20-30.
60. Tenchov R, Bird R, Curtze AE, Zhou Q. Lipid nanoparticles - from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano 2021;15:16982-7015.
61. Mehta M, Bui TA, Yang X, Aksoy Y, Goldys EM, Deng W. Lipid-based nanoparticles for drug/gene delivery: an overview of the production techniques and difficulties encountered in their industrial development. ACS Mater Au 2023;3:600-19.
62. Zhai J, Fong C, Tran N, Drummond CJ. Non-lamellar lyotropic liquid crystalline lipid nanoparticles for the next generation of nanomedicine. ACS Nano 2019;13:6178-206.
63. Fornasier M, Murgia S. Non-lamellar lipid liquid crystalline nanoparticles: a smart platform for nanomedicine applications. Front Soft Matter 2023;3:1109508.
64. Lancelot A, Sierra T, Serrano JL. Nanostructured liquid-crystalline particles for drug delivery. Expert Opin Drug Deliv 2014;11:547-64.
65. Mahmoud K, Swidan S, El-Nabarawi M, Teaima M. Lipid based nanoparticles as a novel treatment modality for hepatocellular carcinoma: a comprehensive review on targeting and recent advances. J Nanobiotechnol 2022;20:109.
66. Kumar R, Dkhar DS, Kumari R, et al. Lipid based nanocarriers: production techniques, concepts, and commercialization aspect. J Drug Deliv Sci Tec 2022;74:103526.
67. Chaudhuri A, Kumar DN, Shaik RA, et al. Lipid-based nanoparticles as a pivotal delivery approach in triple negative breast cancer (TNBC) therapy. Int J Mol Sci 2022;23:10068.
68. Jia Y, Wang X, Li L, Li F, Zhang J, Liang XJ. Lipid nanoparticles optimized for targeting and release of nucleic acid. Adv Mater 2024;36:e2305300.
69. Xu L, Wang X, Liu Y, Yang G, Falconer RJ, Zhao CX. Lipid nanoparticles for drug delivery. Adv NanoBiomed Res 2022;2:2100109.
70. Varghese R, Salvi S, Sood P, Kulkarni B, Kumar D. Cubosomes in cancer drug delivery: a review. Colloid Interfac Sci 2022;46:100561.
71. Zhang Z, Yao S, Hu Y, Zhao X, Lee RJ. Application of lipid-based nanoparticles in cancer immunotherapy. Front Immunol 2022;13:967505.
72. Hussain Z, Khan S, Imran M, Sohail M, Shah SWA, de Matas M. PEGylation: a promising strategy to overcome challenges to cancer-targeted nanomedicines: a review of challenges to clinical transition and promising resolution. Drug Deliv Transl Res 2019;9:721-34.
73. Anarjan F. Active targeting drug delivery nanocarriers: ligands. Nano Struc Nano Objects 2019;19:100370.
74. Alshaer W, Hillaireau H, Fattal E. Aptamer-guided nanomedicines for anticancer drug delivery. Adv Drug Deliv Rev 2018;134:122-37.
75. Guo Y, Wang Z, Shi X, Shen M. Engineered cancer cell membranes: an emerging agent for efficient cancer theranostics. Exploration 2022;2:20210171.
76. Wang J, Li Y, Nie G. Multifunctional biomolecule nanostructures for cancer therapy. Nat Rev Mater 2021;6:766-83.
77. García-Pinel B, Porras-Alcalá C, Ortega-Rodríguez A, et al. Lipid-based nanoparticles: application and recent advances in cancer treatment. Nanomaterials 2019;9:638.
78. Dilliard SA, Siegwart DJ. Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs. Nat Rev Mater 2023;8:282-300.
79. Xue X, Qu H, Li Y. Stimuli-responsive crosslinked nanomedicine for cancer treatment. Exploration 2022;2:20210134.
80. Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 1965;13:238-52.
81. Akbarzadeh A, Rezaei-Sadabady R, Davaran S, et al. Liposome: classification, preparation, and applications. Nanoscale Res Lett 2013;8:102.
82. Chen Y, Cheng Y, Zhao P, et al. Co-delivery of doxorubicin and imatinib by pH sensitive cleavable PEGylated nanoliposomes with folate-mediated targeting to overcome multidrug resistance. Int J Pharm 2018;542:266-79.
83. Yue G, Wang C, Liu B, et al. Liposomes co-delivery system of doxorubicin and astragaloside IV co-modified by folate ligand and octa-arginine polypeptide for anti-breast cancer. RSC Adv 2020;10:11573-81.
84. Gladkikh DV, Sen Kova AV, Chernikov IV, et al. Folate-equipped cationic liposomes deliver anti-MDR1-siRNA to the tumor and increase the efficiency of chemotherapy. Pharmaceutics 2021;13:1252.
85. Sriraman SK, Salzano G, Sarisozen C, Torchilin V. Anti-cancer activity of doxorubicin-loaded liposomes co-modified with transferrin and folic acid. Eur J Pharm Biopharm 2016;105:40-9.
86. Fu J, Li W, Xin X, Chen D, Hu H. Transferrin-modified nanoliposome codelivery strategies for enhancing the cancer therapy. J Pharm Sci 2020;109:2426-36.
87. Wang Y, Zhou J, Qiu L, et al. Cisplatin-alginate conjugate liposomes for targeted delivery to EGFR-positive ovarian cancer cells. Biomaterials 2014;35:4297-309.
88. Cui S, Ni Y, Zhao Y, et al. Epidermal growth factor receptor-targeted immunomagnetic liposomes for circulating tumor cell enumeration in non-small cell lung cancer treated with epidermal growth factor receptor-tyrosine kinase inhibitors. Lung Cancer 2019;132:45-53.
89. Burande AS, Viswanadh MK, Jha A, et al. EGFR targeted paclitaxel and piperine co-loaded liposomes for the treatment of triple negative breast cancer. AAPS PharmSciTech 2020;21:151.
90. Liu Y, Li X, Pen R, et al. Targeted delivery of irinotecan to colon cancer cells using epidermal growth factor receptor-conjugated liposomes. Biomed Eng Online 2022;21:53.
91. Pereira SGT, Hudoklin S, Kreft ME, Kostevsek N, Stuart MCA, Al-Jamal WT. Intracellular activation of a prostate specific antigen-cleavable doxorubicin prodrug: a key feature toward prodrug-nanomedicine design. Mol Pharm 2019;16:1573-85.
92. Mizutani K, Kawakami K, Fujita Y, et al. Gene therapy of prostate cancer using liposomes containing perforin expression vector driven by the promoter of prostate-specific antigen gene. Sci Rep 2022;12:1442.
93. Ghandhariyoun N, Jaafari MR, Nikoofal-Sahlabadi S, Taghdisi SM, Moosavian SA. Reducing Doxorubicin resistance in breast cancer by liposomal FOXM1 aptamer: in vitro and in vivo. Life Sci 2020;262:118520.
94. de Freitas CF, Montanha MC, Pellosi DS, Kimura E, Caetano W, Hioka N. “Biotin-targeted mixed liposomes: a smart strategy for selective release of a photosensitizer agent in cancer cells”. Mater Sci Eng C Mater Biol Appl 2019;104:109923.
95. Lu R, Zhou L, Yue Q, et al. Liposomes modified with double-branched biotin: a novel and effective way to promote breast cancer targeting. Bioorg Med Chem 2019;27:3115-27.
96. Li R, Peng Y, Pu Y, et al. Fructose and biotin co-modified liposomes for dual-targeting breast cancer. J Liposome Res 2022;32:119-28.
97. Singh P, Singh N, Mishra N, et al. Functionalized bosutinib liposomes for target specific delivery in management of estrogen-positive cancer. Colloids Surf B Biointerfaces 2022;218:112763.
98. Matusewicz L, Podkalicka J, Sikorski AF. Immunoliposomes with simvastatin as a potential therapeutic in treatment of breast cancer cells overexpressing HER2 - an in vitro study. Cancers 2018;10:418.
99. Kim B, Shin J, Wu J, et al. Engineering peptide-targeted liposomal nanoparticles optimized for improved selectivity for HER2-positive breast cancer cells to achieve enhanced in vivo efficacy. J Control Release 2020;322:530-41.
100. Chen IJ, Cheng YA, Ho KW, et al. Bispecific antibody (HER2 × mPEG) enhances anti-cancer effects by precise targeting and accumulation of mPEGylated liposomes. Acta Biomater 2020;111:386-97.
101. Li L, He D, Guo Q, et al. Exosome-liposome hybrid nanoparticle codelivery of TP and miR497 conspicuously overcomes chemoresistant ovarian cancer. J Nanobiotechnology 2022;20:50.
102. Zhang J, Du Z, Pan S, et al. Overcoming multidrug resistance by codelivery of MDR1-targeting siRNA and doxorubicin using EphA10-mediated pH-sensitive lipoplexes: in vitro and in vivo evaluation. ACS Appl Mater Interfaces 2018;10:21590-600.
103. Liu C, Zhao Z, Gao R, et al. Matrix metalloproteinase-2-responsive surface-changeable liposomes decorated by multifunctional peptides to overcome the drug resistance of triple-negative breast cancer through enhanced targeting and penetrability. ACS Biomater Sci Eng 2022;8:2979-94.
104. Wang P, Wang Y, Xia X, Huang W, Yan D. Redox-responsive drug-inhibitor conjugate encapsulated in DSPE-PEG2k micelles for overcoming multidrug resistance to chemotherapy. Biomater Sci 2023;11:4335-45.
105. Zhu Y, Zhang G, Li M, Ma L, Huang J, Qiu L. Ultrasound-augmented phase transition nanobubbles for targeted treatment of paclitaxel-resistant cancer. Bioconjug Chem 2020;31:2008-20.
106. Chen J, Fang C, Chang C, et al. Ultrasound-propelled liposome circumvention and siRNA silencing reverse BRAF mutation-arised cancer resistance to trametinib. Colloids Surf B Biointerfaces 2024;234:113710.
107. Li X, Wu X, Yang H, Li L, Ye Z, Rao Y. A nuclear targeted Dox-aptamer loaded liposome delivery platform for the circumvention of drug resistance in breast cancer. Biomed Pharmacother 2019;117:109072.
108. Haggag Y, Abu Ras B, El-Tanani Y, et al. Co-delivery of a RanGTP inhibitory peptide and doxorubicin using dual-loaded liposomal carriers to combat chemotherapeutic resistance in breast cancer cells. Expert Opin Drug Deliv 2020;17:1655-69.
109. Li Y, Tan X, Liu X, et al. Enhanced anticancer effect of doxorubicin by TPGS-coated liposomes with Bcl-2 siRNA-corona for dual suppression of drug resistance. Asian J Pharm Sci 2020;15:646-60.
110. Shen Q, Shen Y, Jin F, Du YZ, Ying XY. Paclitaxel/hydroxypropyl-β-cyclodextrin complex-loaded liposomes for overcoming multidrug resistance in cancer chemotherapy. J Liposome Res 2020;30:12-20.
111. Yin W, Zhao Y, Kang X, et al. BBB-penetrating codelivery liposomes treat brain metastasis of non-small cell lung cancer with EGFRT790M mutation. Theranostics 2020;10:6122-35.
112. Sun M, Xie H, Zhang W, et al. Bioinspired lipoproteins of furoxans-gemcitabine preferentially targets glioblastoma and overcomes radiotherapy resistance. Adv Sci 2024;11:e2306190.
113. Wang Y, Wang Z, Jia F, et al. CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment. Bioact Mater 2022;17:147-61.
114. Zhu Y, Wang A, Zhang S, et al. Paclitaxel-loaded ginsenoside Rg3 liposomes for drug-resistant cancer therapy by dual targeting of the tumor microenvironment and cancer cells. J Adv Res 2023;49:159-73.
115. Zhu YX, Jia HR, Duan QY, et al. Photosensitizer-doped and plasma membrane-responsive liposomes for nuclear drug delivery and multidrug resistance reversal. ACS Appl Mater Interfaces 2020;12:36882-94.
116. Wu J, Wang F, Dong J, et al. Therapeutic response of multifunctional lipid and micelle formulation in hepatocellular carcinoma. ACS Appl Mater Interfaces 2022;14:45110-23.
117. Bai F, Yin Y, Chen T, et al. Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer. Int J Nanomedicine 2018;13:1327-39.
118. Baglo Y, Liang BJ, Robey RW, Ambudkar SV, Gottesman MM, Huang HC. Porphyrin-lipid assemblies and nanovesicles overcome ABC transporter-mediated photodynamic therapy resistance in cancer cells. Cancer Lett 2019;457:110-8.
119. Saw PE, Park J, Jon S, Farokhzad OC. A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin. Nanomedicine 2017;13:713-22.
120. Subhan MA, Attia SA, Torchilin VP. Advances in siRNA delivery strategies for the treatment of MDR cancer. Life Sci 2021;274:119337.
121. Wilson E, Goswami J, Baqui AH, et al; ConquerRSV Study Group. Efficacy and safety of an mRNA-based RSV PreF vaccine in older adults. N Engl J Med 2023;389:2233-44.
122. Moderna Inc. Moderna Receives U.S. FDA approval for RSV vaccine mRESVIA(R). 2024. Available from: https://investors.modernatx.com/news/news-details/2024/Moderna-Receives-U.S.-FDA-Approval-for-RSV-Vaccine-mRESVIAR/default.aspx. [Last accessed on 19 Jun 2024].
123. Zhou F, Huang L, Li S, et al. From structural design to delivery: mRNA therapeutics for cancer immunotherapy. Exploration 2024;4:20210146.
124. Kubiatowicz LJ, Mohapatra A, Krishnan N, Fang RH, Zhang L. mRNA nanomedicine: design and recent applications. Exploration 2022;2:20210217.
125. El Moukhtari SH, Garbayo E, Amundarain A, et al. Lipid nanoparticles for siRNA delivery in cancer treatment. J Controll Release 2023;361:130-46.
126. Pandey PR, Young KH, Kumar D, Jain N. RNA-mediated immunotherapy regulating tumor immune microenvironment: next wave of cancer therapeutics. Mol Cancer 2022;21:58.
127. Makita Y, Teratani M, Murata S, Hoashi Y, Matsumoto S, Kawamata Y. Antitumor activity of kinetochore-associated protein 2 siRNA against lung cancer patient-derived tumor xenografts. Oncol Lett 2018;15:4676-82.
128. Fattore L, Cafaro G, Di Martile M, et al. Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance. Oncogene 2023;42:293-307.
129. Younis MA, Khalil IA, Elewa YH, Kon Y, Harashima H. Ultra-small lipid nanoparticles encapsulating sorafenib and midkine-siRNA selectively-eradicate sorafenib-resistant hepatocellular carcinoma in vivo. J Controll Release 2021;331:335-49.
130. Li C, Li T, Huang L, Yang M, Zhu G. Self-assembled lipid nanoparticles for ratiometric codelivery of cisplatin and siRNA targeting XPF to combat drug resistance in lung cancer. Chem Asian J 2019;14:1570-6.
131. Rosenblum D, Gutkin A, Kedmi R, et al. CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy. Sci Adv 2020;6:eabc9450.
132. Chatterjee S, Naidu GS, Hazan-Halevy I, et al. Therapeutic gene silencing of CKAP5 leads to lethality in genetically unstable cancer cells. Sci Adv 2023;9:eade4800.
133. Ehexige E, Bao M, Bazarjav P, et al. Silencing of STAT3 via peptidomimetic LNP-mediated systemic delivery of RNAi downregulates PD-L1 and inhibits melanoma growth. Biomolecules 2020;10:285.
134. Nakamura T, Sato T, Endo R, et al. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation. J Immunother Cancer 2021;9:e002852.
135. Cho R, Sakurai Y, Jones HS, Akita H, Hisaka A, Hatakeyama H. Silencing of VEGFR2 by RGD-modified lipid nanoparticles enhanced the efficacy of anti-PD-1 antibody by accelerating vascular normalization and infiltration of T cells in tumors. Cancers 2020;12:3630.
136. Bose A, Roy Burman D, Sikdar B, Patra P. Nanomicelles: types, properties and applications in drug delivery. IET Nanobiotechnology 2021;15:19-27.
137. Gao W, Ye G, Duan X, Yang X, Yang VC. Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer. Int J Nanomedicine 2017;12:1047-64.
138. Chen R, Ni S, Chen W, Liu M, Feng J, Hu K. Improved anti-triple negative breast cancer effects of docetaxel by RGD-modified lipid-core micelles. Int J Nanomedicine 2021;16:5265-79.
139. Colombo S, Beck-broichsitter M, Bøtker JP, Malmsten M, Rantanen J, Bohr A. Transforming nanomedicine manufacturing toward Quality by Design and microfluidics. Adv Drug Deliv Rev 2018;128:115-31.
140. Fornaguera C, García-Celma MJ. Personalized nanomedicine: a revolution at the nanoscale. J Pers Med 2017;7:12.
141. Persano F, Gigli G, Leporatti S. Lipid-polymer hybrid nanoparticles in cancer therapy: current overview and future directions. Nano Ex 2021;2:012006.
142. Alavi M, Nokhodchi A. Micro- and nanoformulations of paclitaxel based on micelles, liposomes, cubosomes, and lipid nanoparticles: recent advances and challenges. Drug Discov Today 2022;27:576-84.
143. Chavda VP, Vihol D, Mehta B, et al. Phytochemical-loaded liposomes for anticancer therapy: an updated review. Nanomedicine 2022;17:547-68.
144. Xia Y, Sun M, Huang H, Jin WL. Drug repurposing for cancer therapy. Signal Transduct Target Ther 2024;9:92.
145. Bukhari SI, Imam SS, Ahmad MZ, et al. Recent progress in lipid nanoparticles for cancer theranostics: opportunity and challenges. Pharmaceutics 2021;13:840.
146. Zhang P, Li W, Liu C, et al. Molecular imaging of tumour-associated pathological biomarkers with smart nanoprobe: from “Seeing” to “Measuring”. Exploration 2023;3:20230070.
147. Xin J, Han S, Zheng M, et al. A nitroreductase-responsive nanoprobe with homogeneous composition and high loading for preoperative non-invasive tumor imaging and intraoperative guidance. Chin Chem Lett 2024;35:109165.
148. Craig MA, Jenner AL, Namgung B, Lee LP, Goldman A. Engineering in medicine to address the challenge of cancer drug resistance: from micro- and nanotechnologies to computational and mathematical modeling. Chem Rev 2021;121:3352-89.
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Dechbumroong, P.; Hu R.; Keaswejjareansuk W.; Namdee K.; Liang X. J. Recent advanced lipid-based nanomedicines for overcoming cancer resistance. Cancer. Drug. Resist. 2024, 7, 24. http://dx.doi.org/10.20517/cdr.2024.19
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