Evelopment of Surface Functionalized Carfilzomib Loaded Protein Nanoparticle as Biotherapeutics for the Treatment of Ovarian Cancer

Abstract

Carfilzomib(CFZ) is a second generation irreversible proteosome inhibitor that have shown strong clinical efficacy in relapsed cancer management.Despite of having high newlinepotency in cancer treatment, poor solubility, short half-life, and poor in vivo stability hinders its therapeutic application. Proteins like lactoferrin and transferrin with structural tunability and iron homeostasis resembling multifunctional roles in cancer research, that could enhance the accumulation of drug in vicinity of tumor tissues. Exploring the surface amenities of proteins by conjugating tumor associated antigens(TAAs) can be an emerging approach as newlinecancer theragnostic. Objective:The study aimed to fabricate carfilzomib loaded lactoferrin(LF) or transferrin(TF) nanoparticles(NPs) followed by surface functionalization with different biomarkers such as Folate(FA) or Anti-Her2(AB) to obtain several types of nanostructures such as CFZ-LFNPs, CFZ-TFNPs, FA-CFZ-LF-NPs, AB-CFZ-LF-NPs, and AB-CFZ-TF-NPs against ovarian cancer. Method: Desolvation technique was used to synthesize protein nanoparticles(CFZ-LFNPs and CFZ-TFNPs). Quality-by-design paradigms were used to obtain optimal composition of nanoformulation. Folic acid(FA) or Anti-Her2(AB) functionalized protein nanoconjugates were synthesized using EDC-NHS carbodiimide chemistry and characterized using NMR spectroscopy. Results: The CFZ-LFNPs and CFZTFNPs were found to be uniformly distributed with particle size in range of 100-150nm. The drug newlineloading was found to be 14.14±0.521% and 16.14±0.221%, whereas %entrapment efficiency was found to be 86% ± 0.289 and 93.21% ± 0.209, respectively. CFZ-LF-NPs and CFZ-TFNPs showed slow and prolonged drug release at pH(7.4) and diffusion mediated high drug release at pH(5.5).Whereas, FA conjugated nanoparticles resulted in fast and highest newline%drug release of 91.932 ± 0.549% at tumor pH 5.5, thereby indicating pH triggered drug newlinerelease.