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Bicontinuous Cubic Liquid Crystalline Nanoparticles for Oral Delivery of Doxorubicin: Implications on Bioavailability, Therapeutic Efficacy, and Cardiotoxicity

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Abstract

Purpose

The present study explores the potential of bicontinous cubic liquid crystalline nanoparticles (LCNPs) for improving therapeutic potential of doxorubicin.

Methods

Phytantriol based Dox-LCNPs were prepared using hydrotrope method, optimized for various formulation components, process variables and lyophilized. Structural elucidation of the reconstituted formulation was performed using HR-TEM and SAXS analysis. The developed formulation was subjected to exhaustive cell culture experiments for delivery potential (Caco-2 cells) and efficacy (MCF-7 cells). Finally, in vivo pharmacokinetics, pharmacodynamic studies in DMBA induced breast cancer model and cardiotoxicity were also evaluated.

Results

The reconstituted formulation exhibited Pn3m type cubic structure, evident by SAXS and posed stability in simulated gastrointestinal fluids and at accelerated stability conditions for 6 months. Dox-LCNPs revealed significantly higher cell cytotoxicity (16.23-fold) against MCF-7 cell lines as compared to free drug owing to its preferential localization in the vicinity of nucleus. Furthermore, Caco-2 cell experiments revealed formation of reversible “virtual pathways” in the cell membrane for Dox-LCNPs and hence posed significantly higher relative oral bioavailability (17.74-fold). Subsequently, Single dose of Dox-LCNPs (per oral) led to significant reduction in % tumor burden (~42%) as compared that of ~31% observed in case of Adriamycin® (i.v.) when evaluated in DMBA induced breast cancer model. Moreover, Dox induced cardiotoxicity was also found to be significantly lower in case of Dox-LCNPs as compared to clinical formulations (Adriamycin® and Lipodox®).

Conclusion

Incorporation of Dox in the novel LCNPs demonstrated improved antitumor efficacy and safety profile and can be a viable option for oral chemotherapy.

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Acknowledgments and Disclosures

Authors are thankful to Director, NIPER for providing necessary infrastructure facilities. The work was supported by Council of Scientific and Industrial Research (CSIR), Government of India, New Delhi, India. Authors are also thankful for the technical support rendered by Mr. Rahul Mahajan.

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  1. Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India

    Nitin K. Swarnakar, Kaushik Thanki & Sanyog Jain

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  1. Nitin K. Swarnakar
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Correspondence to Sanyog Jain.

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Swarnakar, N.K., Thanki, K. & Jain, S. Bicontinuous Cubic Liquid Crystalline Nanoparticles for Oral Delivery of Doxorubicin: Implications on Bioavailability, Therapeutic Efficacy, and Cardiotoxicity. Pharm Res 31, 1219–1238 (2014). https://doi.org/10.1007/s11095-013-1244-8

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