Carfilzomib and Paclitaxel Co-Loaded Protein Nanoparticles an Effective Therapy Against Pancreatic Adenocarcinomas

Abstract

Therapeutic efficacy of pancreatic adenocarcinomas (PACs) with combined therapy of carfilzomib (CFZ) and paclitaxel (PTX) co-loaded in human serum albumin (HSA) nanoparticles (NPs) was examined. Methods: CFZ and PTX were encapsulated individually or combined into HSA NPs by a simple reverse self-assembly method developed to achieve an optimal combination ratio for synergistic therapy. CFZ or/and PTX loaded HSA nanoparticles were physically characterized and the evaluation of combination index, drug release, pharmacokinetic, anti-tumor, and biodistribution studies were conducted. Results: All resultant drug-loaded HSA NPs were spherical with a particle size of <150 nm and a zeta potential of −21.1~−23.0 mV. Drug loading rates and entrapment efficiencies were 9.1%~10.1% and 90.7%~97.1%, respectively. CFZ and PTX demonstrated synergistic effects in an MIA PaCa-2 cytotoxicity at a 1:2 ratio (CI 50 were 0.01~0.25). In vitro dissolution revealed that the CFZ/PTX ratio released from the co-loaded HSA NPs (CFZ/PTX/HSA NPs) was about 1.77~2.08, which conformed to the designated loaded ratio. In vivo evaluation showed that the combined therapy of CFZ and PTX at a 1:2 ratio co-loaded in HSA NPs (CFZ/PTX/HSA NPs) demonstrated optimal synergistic improvement of the growth inhibition of MIA PaCa-2 cells with less systematic toxicity, even though the pharmacokinetic profiles observed did not show obvious beneficial and their biodistributions in tumors were found to be smaller. Conclusion:The one-pot reverse assembly method developed was environmentally friendly and capable of co-loading an optimal combination ratio of two chemodrugs into HSA NPs for synergistic therapy.

Carfilzomib relieves pancreatitis-initiated pancreatic ductal adenocarcinoma by inhibiting high-temperature requirement protein A1

“…Carfilzomib blocks the degradation of dysfunctional proteins by irreversibly inhibiting the proteasome in its ChT-L site [ 36 ]. In addition, carfilzomib combined with paclitaxel, ganetespib, or HDAC class IIa selective inhibitor TMP269 have an effective therapy against PC [ 37 – 39 ]. Here, we first reported carfilzomib as a promising small molecule drug that can inhibit HTRA1.…”

Targeting the PD-1/PD-L1 axis for cancer treatment: a review on nanotechnology

“…In a subsequent study, PD-L1 siRNA was encapsulated into human serum albumin (HSA) ( plasmid/stPEI/HSA) NPs. These NPs could be easily internalized and had low cytotoxic effect, leading to a reduction in the expression of PD-L1 by 21.95% in CT26-a mouse colon carcinoma cell line [25].…”