Design and synthesis of nanoformulation for the co delivery of natural phytochemicals and chemotherapeutic drugs against pancreatic cancer

Abstract

A disease is scarier and more dangerous if its presence inside the host is not known; Pancreatic ductal adenocarcinoma (PDAC) is one such disease. PDAC develops inside the host very silently and without showing any response from the host body till it reaches its last stages. Due to limited treatment options available to cure PDAC, survival rates are very low, making it a compulsion to find ways in developing treatment options for patients and increasing survival rates. Taking into consideration these issues related to PDAC, the current study is aimed to find therapeutic options for PDAC in an alternate treatment strategy using natural sources that could possibly bring out good results when used as either monotherapy or combination therapy. A thorough screening of plant phytochemicals was conducted that shortlisted four dietary phytochemicals i.e; caffeic acid (CFA), farnesol (FRN), pentagalloylglucose (PGG) and plumbagin (PLGN) as potent drug candidates for PDAC. These selected phytochemicals were further studied in detail as drug candidates against PDAC targets, following which these were commercially procured and tested in-vitro on PDAC cell lines. Several cell culture-based assays showed that CFA, PGG and PLGN were more effective and also had anti-migratory effects. However, in gene expression analysis PGG showed certain resistance supportive mechanisms, so only CFA and PLGN were used to explore their benefits as combination therapy. To achieve this, CFA and PLGN were combined with gemcitabine (Gem) and doxorubicin (Dox) where both showed antagonistic effect with both chemotherapeutic drugs. To overcome this antagonism, pre-sensitizing approach was taken up and was successful with Dox in case of both CFA and PLGN. Also, it was seen that ROS generation was increased with pre-sensitizing effect. Further, in order to resolve another issue related to drug delivery PLGA nanoparticles were synthesized in a way to carry both Dox and PLGN. In this, Dox was conjugated to PLGA and the PLGN was loaded into the conjugate