Cabazitaxel and camptothecin co-loaded in pH-sensitive transferrin-targeted, PEGylated cholesterol-based poly(amidoamine) dendrimers as a synergistic combination for prostate cancer.

Abstract

The clinical utility of combining cabazitaxel (CBZ) and camptothecin (CPT) for advanced prostate cancer is hindered by emerging drug resistance and the absence of optimized nanocarriers for co-delivery. We investigated the potential of novel Tf-targeted nanocarriers to encapsulate CBZ and CPT, aiming to selectively augment their synergistic anti-cancer activity within in vitro prostate cancer models. Our findings demonstrate a robust synergistic interaction between CBZ and CPT (with a growth inhibition percentage of 87.42% and a combination index of 0.12) in PC3-Luc cells at CBZ:CPT molar ratio of 1:8. Transferrin-bearing PEGylated cholesterol-based poly(amidoamine) dendrimers were successfully synthesized and observed their assembly at a threshold aggregation concentration of around 10 µg/mL. CBZ was encapsulated with 88.35% efficiency and over 70% of the payload released under acidic tumor conditions (pH 5.5-6.4). When fluorescent CBZ was mixed with CPT and delivered by Tf-targeted PPSSCH, its cellular uptake among PC3-Luc, DU145, and LNCaP cells enhanced by 16.50-, 17.20-, and 21.18-times, respectively. Encapsulation of the CBZ/CPT combination using optimized synergistic ratio within transferrin-functionalized, PEGylated cholesterol-based poly(amidoamine) dendrimers significantly potentiated the antiproliferative activity of CBZ by 3.93-, 4.72-, and 5.06-fold in these three cell lines, respectively. These promising in vitro findings support further preclinical (in vivo) evaluation of transferrin-targeted PEGylated cholesterol-based PAMAM dendrimers for CBZ-CPT co-delivery.