4.7 Article

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

Journal

INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 606, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.ijpharm.2021.120866

Keywords

Polymeric micelle; Doxorubicin; All-trans retinoic acid; Breast cancer

Funding

  1. Council of Scientific and Industrial Research [CSIR-37 (1722) /19/EMR-II]
  2. DST-SERB, New Delhi, India [CRG/2018/001065]
  3. DST-FIST [SR/FST/LS-II/2018/210]
  4. Department of Pharmacy, BITS-Pilani, Hyderabad, India

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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.
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.

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