Targeted Delivery Polymeric Nanosystem Reinforced by Synergism of Embilin and RPI-1 for Therapeutics of Pancreatic Cancer

Pancreatic cancer (PC) is an aggressive form of malignancy with poor prognosis and feeble survival benefits. Here, we have ventured a personalized nanoconstruct constituted of the synergistic therapeutic benefit of two agents, namely, embelin and RPI-1, coloaded in a biodegradable nanodelivery system which has been tethered with a targeting peptide substrate for plectin-1, a surface biomarker of PC. The phytomolecule embelin, an alkyl-substituted hydroxyl benzoquinone isolated from the seeds of Embelia ribes, is introduced in this combination therapy and is known as a natural inhibitor of X-linked inhibitor of apoptosis protein and executes anticancer activity via the NF-kB pathway. On the other hand, tyrosine-protein kinase Met (c-MET) is a biomarker of PC wherein the molecule RPI-1, an indolinone derivative, is selective to the c-MET inhibitor. After conducting a series of systematic cytotoxicity evaluations followed by enumeration of combination index, a standalone synergic ratio of embelin and RPI-1 (1: 4.7) was evolved that executed a benchmarked PC-selective toxicity profile. This composition was precisely incorporated within a PC-targeted PLGA–chitosan core–shell nanoparticle delivery system for avoiding collateral damages. Appealing features of the nanoconstruct including biocompatibility, PC-targeted uptake, and subsequent execution of cytotoxicity and antimetastatic properties have been systematically evaluated on the PC cell line PANC-1 and later on the xenograft PC model of zebra fish. Finally, the unique metabolic changes associated with the therapeutic action of embelin and RPI-1 was scrutinized by surface-enhanced Raman spectroscopy and liquid chromatography–mass spectrometry analysis wherein almost 25 metabolites associated with the cell death pathway deciphered a significant variation. Therefore, this proof-of-concept personalized nanodelivery warrants further preclinical and clinical evaluations for the management of PC.