Formulation of Acid-Sensitive Micelles for Delivery of Cabazitaxel into Prostate Cancer Cells

Aydin O., YOUSSEF I., Durmaz Y. Y., TİRUCHİNAPALLY G., ElSayed M. E. H.

MOLECULAR PHARMACEUTICS, cilt.13, sa.4, ss.1413-1429, 2016 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 13 Sayı: 4
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1021/acs.molpharmaceut.6b00147
  • Dergi Adı: MOLECULAR PHARMACEUTICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1413-1429
  • Anahtar Kelimeler: amphiphilic polymers, acid-sensitive micelles, acid-labile linkers, cabazitaxel controlled release, prostate cancer, drug delivery, PHASE-III TRIAL, POLYMERIC MICELLES, INTRACELLULAR DELIVERY, IN-VITRO, PACLITAXEL, DOCETAXEL, DOXORUBICIN, NANOPARTICLES, COPOLYMERS, TAXANE
  • Erciyes Üniversitesi Adresli: Hayır

Özet

We report the synthesis of an amphiphilic triblock copolymer composed of a hydrophilic polyethylene glycol) (PEG) block, a central poly(acrylic acid) (PAA) block, and a hydrophobic poly(methyl methacrylate) (PMMA) block using atom transfer radical polymerization technique. We examined the self-assembly of PEG-b-PAA-b-PMMA copolymers in aqueous solutions forming nanosized micelles and their ability to encapsulate hydrophobic guest molecules such as Nile Red (NR) dye and cabazitaxel (CTX, an anticancer drug). We used 2,2 beta'-(propane-2,2-diylbis(oxy))-diethanamine to react with the carboxylic acid groups of the central PAA block forming acid-labile, shell cross-linked micelles (SCLM). We investigated the loading efficiency and release of different guest molecules from non-cross-linked micelles (NSCLM) and shell cross-linked micelles (SCLM) prepared by reacting 50% (SCLM-50) and 100% (SCLM-100) of the carboxylic acid groups in the PAA in physiologic (pH 7.4) and acidic (pH 5.0) buffer solutions as a function of time. We examined the uptake of NR-loaded NSCLM, SCLM-50, and SCLM-100 micelles into PC-3 and C4-2B prostate cancer cells and the effect of different micelle compositions on membrane fluidity of both cell lines. We also investigated the effect of CTX-loaded NSCLM, SCLM-50, and SCLM-100 micelles on the viability of PC-3 and C4-2B cancer cells compared to free CTX as a function of drug concentration. Results show that PEG-b-PAA-b-PMMA polymers form micelles at concentrations >= 11 mu g/mL with an average size of 40-50 nm. CTX was encapsulated in PEG-b-PAA-b-PMMA micelles with 55% loading efficiency in NSCLM. In vitro release studies showed that 30% and 85% of the loaded CTX was released from SCLM-50 micelles in physiologic (pH 7.4) and acidic (pH 5.0) buffer solutions over 30 h, confirming micelles' sensitivity to solution pH. Results show uptake of NSCLM and SCLM into prostate cancer cells delivering their chemotherapeutic cargo, which triggered efficient cancer cell death. PEG-b-PAA-b-PMMA micelles were not hemolytic and did not cause platelet aggregation, which indicate their biocompatibility.