Bicontinuous cubic liquid crystalline nanoparticles for oral delivery of Doxorubicin: implications on bioavailability, therapeutic efficacy, and cardiotoxicity.

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.

• Authors: Nitin K Swarnakar, Kaushik Thanki, Sanyog Jain
• Journal: Pharmaceutical research (Pharm Res) Vol. 31 Issue 5 Pg. 1219-38 (May 2014) ISSN: 1573-904X [Electronic] United States
• PMID: 24218223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Doxorubicin

Topics

• Administration, Oral
• Antibiotics, Antineoplastic (administration & dosage, adverse effects, pharmacokinetics)
• Biological Availability
• Cell Line, Tumor
• Doxorubicin (administration & dosage, adverse effects, pharmacokinetics)
• Heart (drug effects)
• Humans
• Microscopy, Electron, Transmission
• Nanoparticles
• Scattering, Radiation