Cancer stem cells-emanated therapy resistance Implications for liposomal drug delivery systems

Purpose: Cancer stem cells (CSCs) drive tumor heterogeneity, drug resistance, recurrence, and metastasis, limiting conventional chemo/radiotherapy. Liposomal drug delivery systems (LDDSs) are biocompatible, versatile nanocarriers that may overcome CSC-mediated resistance, but their clinical translation remains limited by biological, manufacturing, and targeting barriers.

Hypothesis: As a review, there is no single experimental hypothesis. Central thesis: if CSC-specific resistance mechanisms are identified and targeted using rationally designed liposomal carriers—alone or in combination with chemo/immunotherapy—then resistant CSCs can be eliminated more effectively, reducing tumor relapse and improving cancer therapy outcomes.

Aims: Describe mechanisms by which CSCs promote drug resistance and impair cancer therapy efficacy. - Summarize each CSC resistance mechanism as a potential therapeutic target. - Review the status, therapeutic potential, and prospects of different liposomal drug delivery systems in overcoming CSC drug resistance. - Discuss challenges and future considerations for clinical translation of LDDSs and CSC-targeted therapies.

Delivery system: Platform: Liposomal drug delivery systems, including conventional liposomes, PEGylated/long-circulating liposomes, cationic liposomes, pH-sensitive, thermo-sensitive, immunoliposomes, niosomes, magnetoliposomes, fusogenic liposomes, and multifunctional liposomes. - Targeting strategies: Passive EPR-based targeting; active targeting with antibodies (anti-EGFR, anti-HER2, anti-TfR, anti-CD44, anti-CD133, anti-CD90), aptamers, peptides (RGD, pHA, TfR-T12, stearyl-R8), RSPO1, hyaluronic acid, and dual-targeted ligands. - Payloads: Doxorubicin, paclitaxel, vinorelbine, parthenolide, salinomycin, chloroquine, disulfiram, all-trans retinoic acid (ATRA), siRNA/miRNA, p53 plasmid DNA, and combined chemo/immunotherapeutic agents. - CSC targets: ALDH, ABC transporters, CD44, CD133, LGR5, EpCAM, CD90, TfR, HER2, EGFR, ECM components, CAFs, and immunosuppressive niche cells.

Approach: Review/synthesis of preclinical and clinical studies. In vitro models include CSC-enriched populations from breast (MCF-7, MDA-MB-231 CD44+/CD24−), liver (HepG2), glioblastoma, colorectal, lung, pancreatic, and ovarian cancers. In vivo models include mouse xenografts, orthotopic models, patient-derived xenografts (PDX), NOD/SCID and BALB/c mice. Clinical data are summarized from ClinicalTrials.gov, including phase I–III trials of CSC-targeting agents and liposomal formulations.

Key methods: Literature-based analysis of CSC resistance mechanisms; CSC marker characterization, mammosphere formation, migration/invasion assays, tumor growth inhibition, survival analysis, imaging, flow cytometry, confocal microscopy, pharmacokinetics/biodistribution, and clinical trial outcome synthesis.

Key results: CSCs resist therapy through autophagy, hypoxia/HIF signaling, CSC niche/CAF/MSC support, ECM remodeling, ALDH detoxification, ABC transporter-mediated efflux, enhanced DNA repair, quiescence, activated Notch/Hh/Wnt/PI3K/AKT/EGFR/JAK-STAT pathways, and anti-apoptotic protein overexpression. - Liposomal co-delivery of vinorelbine and parthenolide achieved >90% tumor growth inhibition in vivo, whereas parthenolide alone had negligible effect on breast cancer stem-like cells. - Dequalinium-surface-modified stealth liposomes loaded with quinacrine and daunorubicin had a size of 98 nm, showed good mitochondrial uptake, induced apoptosis of MCF-7 CSCs and mammospheres, and treated relapsed tumors in NOD/SCID mice. - Of clinically efficacious nanocarrier formulations, only 0.7% of nano drug reached solid tumor cells (not yet evaluated for CSCs), highlighting poor tumor delivery efficiency. - Clinical examples include anti-EGFR immunoliposome-DOX (nontoxic at 50 mg DOX/m² in solid tumors), anti-HER2 MM-302, TfR-targeted SGT-53, and SGT-94.

Interpretation: CSCs are central drivers of therapy resistance, recurrence, and metastasis. Liposomal DDSs offer a versatile platform to overcome CSC resistance through combination therapy, active targeting, ECM/niche modulation, intracellular organelle targeting, and CSC immunotherapy. Clinical translation requires better understanding of CSC heterogeneity, formulation-driven rational development, clinically relevant models, and patient preselection for personalized treatment.

Limitations: This is a review, not a primary study. Clinical translation of LDDSs remains limited by poor tumor accumulation (~0.7% of nano drug reaching solid tumor cells), TME barriers (high interstitial fluid pressure, dense ECM, abnormal vasculature), CSC heterogeneity, off-target effects, incomplete gene knockdown, safety concerns, and challenges in manufacturing, stability, cost, regulation, and sensitive imaging of therapeutic response. CAR-T-based CSC targeting also faces ethical, safety, and homing hurdles.