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Design, Fabrication and Evaluation of Stabilized Polymeric mixed micelles for Effective Management in Cancer Therapy

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Abstract

Purpose

Cancer is one of the most common and fatal disease, chemotherapy is the major treatment against many cancer types. The anti-apoptotic BCL-2 protein’s expression was increased in many cancer types and Venetoclax (VLX; BCL-2 inhibitor) is a small molecule, which selectively inhibits this specified protein. In order to increase the clinical performance of this promising inhibitor as a repurposed drug, polymeric mixed micelles formulations approach was explored.

Methods

The Venetoclax loaded polymeric mixed micelles (VPMM) were prepared by using Pluronic® F-127 and alpha tocopherol polyethylene glycol 1000 succinate (TPGS) as excipients by thin film hydration method and characteristics. The percentage drug loading capacity, entrapment efficiency and in-vitro drug release studies were performed using HPLC method. The cytotoxicity assay, cell uptake and anticancer activities were evaluated in two different cancer cells i.e. MCF-7 (breast cancer) and A-549 (lung cancer).

Results

Particle size, polydispersity index and zeta potential of the VPMM was found to be 72.88 ± 0.09 nm, 0.078 ± 0.009 and -4.29 ± 0.24 mV, respectively. The entrapment efficiency and %drug loading were found to be 80.12 ± 0.23% and 2.13% ± 0.14%, respectively. The IC50 of VLX was found to be 4.78, 1.30, 0.94 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 1.24, 0.68, and 0.314 µg/ml at 24, 48, and 72 h, respectively in A549 cells. Whereas, IC50 of VPMM was found to be 0.42, 0.29, 0.09 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 0.85, 0.13, 0.008 µg/ml at 24, 48 and 72 h in A549 cells, respectively, indicating VPMM showing better anti-cancer activity compared to VLX. The VPMM showed better cytotoxicity which was further proven by other assays and explained the anti-cancer activity is shown through the generation of ROS, nuclear damage,apoptotic cell death and expression of caspase-3,7, and 9 activities in apoptotic cells.

Conclusion

The current investigation revealed that the Venetoclax loaded polymeric mixed micelles (VPMM) revealed the enhanced therapeutic efficacy against breast and lung cancer in vitro models.

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Abbreviations

BCL-2:

B-cell lymphoma-2

BCS:

Biopharmaceutics Classification System

BPMM :

Blank polymeric mixed micelles

CLL:

Chronic Lymphatic Leukemia

CMC:

Critical Micellar Concentration

EGFR:

Epidermal Growth Factor Receptor

ER:

Estrogen Receptor

FITC:

Fluorescein isothiocyanate

HER-2:

Human Epidermal Growth Factor-2

PMM:

Polymeric mixed micelles

PR:

Progesterone Receptor

TPGS:

D-alpha tocopherol PEG1000 succinate

VGFR:

Vascular Endothelial Growth Factor

VLX:

Venetoclax

VPMM:

Venetoclax loaded polymer mixed micelles

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Acknowledgements

Authors would like to acknowledge the Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad (Ministry of Chemical and Fertilizers, India), and grateful thanks to Anamika Sharma, Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, INDIA, for providing extending facilities during this manuscript (Manuscript communication no.: NIPER-H/2022-32).

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Authors and Affiliations

  1. Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India, 500 037

    Padakanti Sandeep Chary, Naveen Rajana, Valamla Bhavana & Neelesh Kumar Mehra

  2. Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India

    Geetanjali Devabattula, Hoshiyar Singh, Chandraiah Godugu, Santosh Kumar Guru & Shashi Bala Singh

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  1. Padakanti Sandeep Chary
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Chary, P.S., Rajana, N., Devabattula, G. et al. Design, Fabrication and Evaluation of Stabilized Polymeric mixed micelles for Effective Management in Cancer Therapy. Pharm Res 39, 2761–2780 (2022). https://doi.org/10.1007/s11095-022-03395-8

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