Self-assembling paclitaxel-mediated stimulation of tumor-associated macrophages for postoperative treatment of glioblastoma

Significance

Combined use of protein drugs with small-molecule therapeutics can synergize their biological and pharmaceutical activities to improve treatment outcomes; however, their differences in molecular characteristics, such as size and water solubility, often lead to challenges in the development of effective drug codelivery systems. In this context, we convert paclitaxel (PTX), a small-molecule anticancer drug of poor water solubility, into a molecular hydrogelator that can be used for local delivery of aCD47, a hydrophilic macromolecular antibody. We show that this “drug-delivered-by-drug” strategy not only combines the distinct material properties of the two therapeutic agents for their long-acting local release, but also synergizes their biological properties to stimulate tumor-associated macrophages with concurrent T cell-mediated immune response for improved tumor treatment.

Abstract

The unique cancer-associated immunosuppression in brain, combined with a paucity of infiltrating T cells, contributes to the low response rate and poor treatment outcomes of T cell-based immunotherapy for patients diagnosed with glioblastoma multiforme (GBM). Here, we report on a self-assembling paclitaxel (PTX) filament (PF) hydrogel that stimulates macrophage-mediated immune response for local treatment of recurrent glioblastoma. Our results suggest that aqueous PF solutions containing aCD47 can be directly deposited into the tumor resection cavity, enabling seamless hydrogel filling of the cavity and long-term release of both therapeutics. The PTX PFs elicit an immune-stimulating tumor microenvironment (TME) and thus sensitizes tumor to the aCD47-mediated blockade of the antiphagocytic “don’t eat me” signal, which subsequently promotes tumor cell phagocytosis by macrophages and also triggers an antitumor T cell response. As adjuvant therapy after surgery, this aCD47/PF supramolecular hydrogel effectively suppresses primary brain tumor recurrence and prolongs overall survivals with minimal off-target side effects.