Transferrin-Conjugated, Camptothecin-Bearing Dendrimersomes Entrapping Docetaxel as a Dual-Drug Nanoplatform for Targeted Prostate Cancer Therapy.

Background/

Objectives

Advanced prostate cancer remains difficult to treat because docetaxel, although clinically important, is limited by systemic toxicity, poor tumor selectivity, and acquired resistance. Camptothecin is a potent anticancer agent, but its clinical application is restricted by poor solubility and instability. This study investigated the synergy between docetaxel and camptothecin and developed transferrin-conjugated, camptothecin-bearing dendrimersomes entrapping docetaxel as a targeted nanocarrier for prostate cancer therapy.

Methods

Drug synergy was evaluated in PC3-Luc cells using an MTT assay and combination index analysis. Transferrin-conjugated, disulfide-linked camptothecin-bearing PEGylated DAB dendrimers were synthesized and characterized by 1H-NMR, critical aggregation concentration analysis, transmission electron microscopy, and entrapment efficiency measurements. pH- and redox-dependent drug release was assessed by dialysis. Cellular uptake and uptake mechanisms were investigated by confocal microscopy, flow cytometry, and inhibitor studies in PC3-Luc, DU145, and LNCaP cells. Anti-proliferative efficacy was determined by an MTT assay.

Results

Docetaxel and camptothecin showed marked synergy in PC3-Luc cells, with a minimum combination index of 0.20 ± 0.01 and 88.10 ± 0.41% growth inhibition at low nanomolar concentrations. Transferrin-conjugated dendrimersomes self-assembled into spherical vesicles with a critical aggregation concentration of approximately 250 µg/mL. They had high docetaxel entrapment efficiency (89.10 ± 0.08%) and enhanced drug release under acidic and reductive conditions. They significantly increased cellular uptake of docetaxel relative to non-targeted dendrimersomes (by up to 3-fold) and free drugs (by up to 20-fold), mainly through transferrin receptor-mediated endocytosis, and improved anti-proliferative activity in all three cell lines. Tf-conjugated DPSSC produced the lowest IC50 values among the tested formulations: 11.72 ± 1.02 nM in PC3-Luc, 9.88 ± 1.22 nM in DU145, and 7.88 ± 1.35 nM in LNCaP cells.

Conclusions

Transferrin-conjugated camptothecin-based dendrimersomes entrapping docetaxel represent a promising multifunctional nanocarrier for prostate cancer that combines synergistic dual-drug therapy, active targeting, and stimulus-responsive release, supporting further evaluation as a selective delivery strategy in advanced prostate cancer using preclinical models and in vivo studies.