PEG-Bottlebrush Stabilizer-Based Worm-like Nanocrystal Micelles with Long-Circulating and Controlled Release for Delivery of a BCR-ABL Inhibitor against Chronic Myeloid Leukemia (CML)

Huamin Liang; Fengming Zou; Liyi Fu; Qingwang Liu; Beilei Wang; Xiaofei Liang; Jing Liu; Qingsong Liu

doi:10.3390/pharmaceutics14081662

Pharmaceutics (Aug 2022)

PEG-Bottlebrush Stabilizer-Based Worm-like Nanocrystal Micelles with Long-Circulating and Controlled Release for Delivery of a BCR-ABL Inhibitor against Chronic Myeloid Leukemia (CML)

Huamin Liang,
Fengming Zou,
Liyi Fu,
Qingwang Liu,
Beilei Wang,
Xiaofei Liang,
Jing Liu,
Qingsong Liu

Affiliations

Huamin Liang: Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
Fengming Zou: Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
Liyi Fu: Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
Qingwang Liu: Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
Beilei Wang: Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
Xiaofei Liang: Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
Jing Liu: Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
Qingsong Liu: Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China

DOI: https://doi.org/10.3390/pharmaceutics14081662
Journal volume & issue: Vol. 14, no. 8
p. 1662

Abstract

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Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic co-polymer, poly oligo(ethylene glycol) methacrylate-b-poly(styrene–co-4-formylphenyl methacrylate) (POEGMA-b-P (St-co-FPMA), PPP), characterized by a hydrophilic part with bottlebrush-like oligo(ethylene glycol) methacrylate (OEGMA) side chains, was synthesized as stabilizers to fabricate a high-drug-loading nanocrystal micelle (053-PPP NC micelle) using the chronic myeloid leukemia (CML) drug candidate N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053 or 053) as a model drug. The 053-PPP NC micelle was characterized and subjected to in vitro and in vivo studies. It featured a worm-like shape of small size, high drug loading (~50%), high colloidal stability, and controlled release in vitro. The presence of the 053-PPP NC micelle resulted in a long-circulation property and a much higher AUC. The 053-PPP NC micelle induced higher accumulation in the tumor tissues under multiple continuous administration. For in vivo efficacy, the 053-PPP NC micelle with a longer dosing interval (96 h), beneficial for improving patient adherence, demonstrated superiority to the 053-F127 NC. The proposed stabilizer PPP and the 053-PPP NC micelle with high drug loading enables drug delivery with long circulation and controlled release of drugs. It is also promising for the development of more efficient nanocrystal-based intravenous injection formulations for poorly water-soluble drugs. It might also offer new possibilities for potential clinical application of the CML candidate drug 053.

Published in Pharmaceutics

ISSN: 1999-4923 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceutics/

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