Developing Novel Anti-Hypoxic Therapy for Pancreatic Cancer by Ph-Sensitive Nanoparticles Carrying Sitravatinib to Enhance Treatment Response to Anti-Pd-1 Therapy( II )

Pancreatic cancer exhibits several features leading to disorganized, dense stroma, leaky, nonfunctional vasculature, series of molecular aberrations and deregulated cellular transport proteins leading to hypoxia and futile drug delivery, chemoresistance and even resistance to immunotherapy. As targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy, our aim is to target hypoxia to improve cancer responsive to immune checkpoint inhibitors. TAM (TYRO3,AXL, MerTK) receptors are key activating signaling nodes in the tumor microenvironment, especially in pancreatic cancer. A novel inhibitor for TAM receptors, sitravatinib, is currently under clinical trial, instead of pancreatic cancer. Given the contribution of TAM receptors to the immunosuppressive state in pancreatic cancer, we will investigate the use of sitravatinib, combined with PD1 antibody, to treat pancreatic cancer.
In our results, sitravatinib promoted M2 macrophage polarization to become M1 subtype. Moreover, sitravatinib reversed resistence to anti-PD-1 antibody in subcutaneous murine pancreatic cancer model via macrophage polarization to M1 subtype. We have ability to design GSH-sensitive nanopolymer delivery anti-cancer drugs (Pharmaceutics 2020, 12 (8): 0778). Therefore, we are going to develop new pHsensitive based nanoparticle carrier as targeting hypoxic TME to carry sitravatinib and remodel tumor-associated macrophages (TAMs) population to enhance therapeutic effect of anti-PD1. In addition, integrin expression strongly promotes cancer cells metastasis in human. Other study has shown the 3 subunit of integrin V3 plays a critical role in M2 polarization regulation. Currently, we have proved the strongly expression of CD61 in both Raw264.7 and Pan 02 cells. RGD is a common tripeptide that recognizes the integrin 3 subunit. Cyclic RGD with the additional yk motif is known to potentially inhibit 3 integrin expression. By formulation of the surface decoration of RGDyk on PLGA nanoparticle with sitravatinib, therapeutic effect may be observed to active the M1 polarization of TAM and suppress the cancer cells metastasis at the same time. Consequently, the nanoformulated sitravatinib was encapsulated into PEGylated liposome with an outside exposure of cyclicRGDyk. The current results show the successful formulation of cyclic-RGDyk modified PLGA@ PEGylated liposome. In C57BL/6 animal model bearing subcutaneous PAN02 tumor, cyclic RGDyk-guided liposome has been proved to target pancreatic cancer tumor. In our preliminary data, combined with PD-1 antibody, cyclic-RGDyk modified PLGA@ PEGylated liposome encapsulated sitravatinib has proved their efficacy against pancreatic cancer.