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Abstract
The purpose of this study was to develop a novel synthetic high-density lipoprotein (sHDL) nanoparticle delivery system for 10-hydroxycamptothecin (HCPT) for treatment of colon carcinoma. HDL is recognized by scavenger receptor B-I (SR-BI) over-expressed in colon carcinomas 5- to 35-fold relative to the human fibroblasts. The sHDL nanoparticles were composed of apolipoprotein A-I mimic peptide (5A) and contained 0.5%–1.5% (w/w) of HCPT. An optimized HCPT-sHDL formulation exhibited 0.7% HCPT loading with 70% efficiency with an average size of 10–12 nm. Partitioning of HCPT in the sHDL lipid membrane enhanced drug stability in its active lactone form, increased solubilization, and enabled slow release. Cytotoxicity studies in HT29 colon carcinoma cells revealed that the IC50 of HCPT-sHDL was approximately 3-fold lower than that of free HCPT. Pharmacokinetics in rats following intravenous administration showed that the area under the serum concentration-time curve (AUC0−t) and Cmax of HCPT-HDL were 2.7- and 6.5-fold higher relative to the values for the free HCPT, respectively. These results suggest that sHDL-based formulations of hydrophobic drugs are useful for future evaluation in treatment of SR-BI-positive tumors.
Acknowledgments
The authors would like to acknowledge Dr Georgios Skiniotis and Ms Annie Dosey from Life Sciences Institute of University of Michigan for their help with TEM imaging.
Disclosure
This work was supported by the University of Michigan’s Michigan Translational Research and Commercialization (MTRAC) grant, NIH R21NS091555, and an Upjohn research award to AS. YY was supported by a grant 81202481 from National Natural Science for Youth Foundation of China, grant L2015527 of Education Department of Liaoning Province, and Scientific Research Foundation for the Returned Overseas Chinese Scholars by State Education Ministry and Shenyang Pharmaceutical University grant GGJJ2014102. The authors report no other conflicts of interest in this work.