Abstract 3680: Albumin-chitosan hybrid onconase nanocarriers for mesothelioma therapy

Abstract

Abstract Onconase (ONC) is a member of a ribonuclease superfamily that has potent cytostatic activity against malignant mesothelioma (MM). However, the recent clinical trials have failed due to unfavorable biopharmaceutical characteristics. The objective of this investigation was to develop BSA-chitosan based hybrid nanoformulations for the efficient delivery of ONC to MM while minimizing the exposure to normal tissues. Taguchi Orthogonal Array L9 type design was used to formulate ONC loaded albumin nanocarriers (ONC-ANC). The ONC-ANC surface was hybridized using varying chitosan concentrations ranging between 0.100-0.175%w/v to form various ONC loaded hybrid nanocarriers (ONC-HNC). The obtained data set was analyzed by principal component analysis (PCA) and principal component regressions (PCR) to decode the effects of investigated design variables. ONC-ANC were found to have a mean particle size of 15.78 ± 0.24 nm (ζ = -21.89 ± 0.11 mV). PCA showed positive correlations between investigated design variables like the bovine serum albumin (BSA) concentration, ethanol dilution, and total ethanol with formulated nanocarrier particle size and entrapment efficiency (EE). PCR showed that the particle size depends on BSA, ethanol dilution, and total ethanol content, while EE was only influenced by BSA content. Further analysis of chitosan and TPP effects used for coating of ONC-ANC by PCR confirmed their positive impacts on the particle size, zeta potential, and prolongation of ONC release compared to uncoated ONC-ANC. PCR analysis of preliminary stability studies showed increase in the particle size and zeta potential at lower pH. However, particle size, zeta potential, and EE of developed HNC were below 63 nm, 31 mV, and 96%, respectively, indicating their stability under subjected buffer conditions. Out of the developed formulations, HNC showed enhanced inhibition of cell viability with lower IC50 against human MM-REN cells compared to ONC and ONC-ANC. This might be attributed to the better cell uptake of HNC, which was confirmed in the cell uptake fluorescence studies. These studies indicated that a developed nanotherapeutic approach might prove beneficial in reducing the therapeutic dose of ONC, minimizing adverse side effects by limiting the exposure of ONC to normal tissues, and help in the development of new therapeutic formulations and routes of administration. Citation Format: Rakesh K. Tekade, Susanne R. Youngren-Ortiz, Haining Yang, Rahul Haware, Mahavir B. Chougule. Albumin-chitosan hybrid onconase nanocarriers for mesothelioma therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3680. doi:10.1158/1538-7445.AM2015-3680