Polymeric micelles of a copolymer composed of all-trans retinoic acid, methoxy-poly(ethylene glycol), and b-poly(N-(2 hydroxypropyl) methacrylamide) as a doxorubicin-delivery platform and for combination chemotherapy in breast cancer

Delivery of combination chemotherapeutic agents to the tumor via nanovesicles has the potential for superior tumor suppression and reduced toxicity. Herein, we prepare a block copolymer (mPH-RA) composed of methoxypoly(ethylene glycol) (mPEG), b-poly(N-(2 hydroxypropyl) methacrylamide) (pHPMA), and all-trans retinoic acid (ATRA) by conjugating ATRA to the pre-formed copolymer, mPEG-b-pHPMA(mP-b-pH). Doxorubicin-loaded micelles, Dox@mP-b-pH, and Dox@mPH-RA were characterized by determining particle size, zeta potential, % DL, EE, Dox release, hemolysis study, and by DSC. The Dox@mPH-RA micelles (mPH-RA: Dox ratios of 10:0.5-2) displayed nano-size (36-45 nm), EE. 26-74%, and DL. 2.9-5.6%. Dox@mPH-RA micelles displayed the highest penetrability and cytotoxicity than free Dox and Dox@mP-b-pH micelles in breast cancer cell lines. Dox@mPHRA exhibited the highest induction of apoptosis (94.1 +/- 3%) than Dox (52.1 +/- 4.5%), and Dox@mP-b-pH (81.7 +/- 3%), and arrested cells in the highest population in G2 and S phase. Dox@mPH-RA increased the t(1/2) and C-max of Dox and demonstrated improved therapeutic efficacy and highest Dox distribution to the tumor. The Dox@mPH-RA increased the levels of apoptosis markers, caspase 3, 7, Ki-67, and caused the highest DNA fragmentation. The presence of RA improved the micelles' physicochemical properties, Dox-loading ability, and the therapeutic potential in Dox@mPH-RA via the combination therapeutic strategy.

Automated summary

Delivery of combination chemotherapeutic agents to tumors using nanovesicles shows promise for enhanced tumor suppression and reduced toxicity. These novel micelles exhibit improved anti-tumor efficacy and cytotoxicity, with higher induction of apoptosis and cellular arrest in G2 and S phase compared to traditional drugs.