Category: Preclinical Development
Purpose: The purpose of this study was to design a nanoplatform self-assembled from a transferrin (Tf)-paclitaxel (PTX) (Tf-PTX) prodrug and marimastat (MATT)-loaded thermosensitive liposomes (LTSLs) (MATT-LTSLs) for the dual targeting of the cancer cells and tumor microenvironment(TME).
Methods: Transferrin (Tf)-paclitaxel (PTX) (Tf-PTX) is a paclitaxel (PTX) targeted prodrug synthesized by our lab. Marimastat can inhibit Matrix metalloproteinases (MMPs) to degrade ECM components. The Tf-PTX/ MATT-LTSLs hybrid nanoparticles (HNPs) were prepared by self-assembling the prodrug Tf-PTX with these liposomes at a Tf/lipid mass ratio of 1:3. The Dynamic light scattering (DLS) was used to measure the diameter and polydispersity index (PDI) of the nanoplatform. The assembly behavior of pro-drug and liposome was characterized by energy resonance transfer (FRET) technique. 4T1 tumor-bearing mice were used as the disease model. Optical in vivo. imaging were used to evaluate the distribution of the vector in model animals. Confocal imaging and flow cytometry were used to investigate the fate of the nanoplatform. Immunohistochemistry, ELISA, flow cytometry and western blot (WB) were used to detect the expression of IFN-γ, lymphocytes, cytokines and target proteins.
Results: Dynamic light scattering showed the MATT-LTSLs and HNPs were 90−110 nm in diameter with a PDI less than 0.3. FRET was utilized to confirm that Tf-PTX can be assembled on the liposomes. In vivo fluorescence imaging of the 4T1 tumor-bearing BALB/c mice showed that the nanoplatform can target the tumor. The tumor growth curve of mice showed that combination treatment could effective inhibit the tumor growth. Flow cytometry analyses of tumor showed that the combination treatment increased the amount of CD3+ T cells, including memory/effector CD4+ and CD8+ T cells, but not regulatory T cells. Analysis of ELISA showed that our treatment increases expression of T cell-stimulating factors such as interleukin (IL)-2 and IFN-γ and decrease the expression of T cell-suppression factors such as TGF-β.
Conclusion: We show that by co-delivery of paclitaxel and marimastat, the nanoplatform can effective inhibit the growth of tumor and increases T cell, recruiting effector/memory T cells into tumors, and target to achieve chemotherapy-immune combination therapy, which could be a promising route for cancer treatment.