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QbD-based development of α-linolenic acid potentiated nanoemulsion for targeted delivery of doxorubicin in DMBA-induced mammary gland carcinoma: in vitro and in vivo evaluation

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Abstract

Breast cancer is the most common cancer of occurrence in women and has the highest mortality incidence rate therein. The present study envisaged to develop doxorubicin (Dox) loaded folate functionalized nanoemulsion (NE) for profound therapeutic activity against mammary gland cancer. NE was prepared using pseudo-ternary phase diagrams utilizing α-linolenic acid (ALA) as lipid phase, to further enhance the anticancer potential of Dox. Box-Behnken design was employed to systematically develop the NE. Optimized NE (f-Dox-NE) was evaluated for in vitro and in vivo performance. f-Dox-NE, with globule size 55.2 ± 3.3 nm, zeta potential − 31 ± 2 mV, entrapment 92.51 ± 3.62%, drug loading 0.42 ± 0.08% and percent drug release 94.86 ± 1.87% in 72 h, was capable of reducing cell viability in MCF-7 cell lines vis-à-vis pure and marketed drug. Further, mechanistic studies in MCF-7 cell lines demonstrated that f-Dox-NE induces cellular apoptosis by reactive oxygen species generated and mitochondrial membrane mediated apoptosis. The antitumor effect was evaluated in 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland tumor in female Albino Wistar rats. f-Dox-NE exhibited enhanced antitumor targeting potential, therapeutic safety and efficacy vis-à-vis pure and marketed drug, as revealed by tumor volume, animal survival, weight variation, cardiotoxicity and biodistribution studies. f-Dox-NE restored the biochemical parameters viz., SOD, catalase, TBARS and protein carbonyl, towards normal levels in comparison to DMBA induced animal group. f-Dox-NE displayed downregulation of anti-apoptotic (Bcl-2 and MMP-9) proteins and upregulation of pro-apoptotic proteins (caspase-9 and BAX). The experimental results suggest that ALA augmented folate functionalized NE are able to overcome the challenges of develo** safe and effective delivery system with enhanced potential for mammary gland carcinoma therapy.

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Acknowledgements

The authors acknowledge the kind support of Miracalus Pharma, India, for providing the gift sample of the drug. Authors also acknowledge the USIC, BBAU Lucknow, India and Aakar Biotechnologies Pvt. Ltd., Lucknow, India, for providing evaluation and characterization facilities for the current research work.

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  1. Department of Pharmaceutical Sciences, School of Biosciences & Biotechnology, Babasaheb Bhimrao Ambedkar University (A Central University), Vidya Vihar, Rae Bareli Road, Lucknow, 226025, India

    Chandra Bhushan Tripathi, Poonam Parashar, Malti Arya, Mahendra Singh, Jovita Kanoujia, Gaurav Kaithwas & Shubhini A. Saraf

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  1. Chandra Bhushan Tripathi
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Correspondence to Shubhini A. Saraf.

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Tripathi, C.B., Parashar, P., Arya, M. et al. QbD-based development of α-linolenic acid potentiated nanoemulsion for targeted delivery of doxorubicin in DMBA-induced mammary gland carcinoma: in vitro and in vivo evaluation. Drug Deliv. and Transl. Res. 8, 1313–1334 (2018). https://doi.org/10.1007/s13346-018-0525-5

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