Efficient treatment of colon cancer with codelivery of TRAIL and imatinib by liposomes.

To solve the problem of resistance of tumor cells to TRAIL and the inevitable side effects of imatinib during treatment, we successfully prepared a kind of multifunctional liposome that encapsulated imatinib in its internal water phase and inserted TRAIL on its membrane in this study, which named ITLPs. The liposomes appeared uniform spherical and the particle size was approximately 150 nm. ITLPs showed high accumulation in TRAIL-resistance cells and HT-29 tumor-bearing mice model. In vitro cytotoxicity assay results showed that the killing activity of HT-29 cells treated with ITLPs increased by 50% and confirmed that this killing activity was mediated by the apoptosis pathway. Through mechanism studies, it was found that ITLPs arrested up to 32.3% of cells in phase M to exert anti-tumor effects. In vivo anti-tumor study showed that ITLPs achieved 61.8% tumor suppression and little toxicity in the HT-29 tumor-bearing mice model. Overall results demonstrated that codelivery of imatinib and TRAIL via liposomes may be a prospective method in the treatment of the TRAIL-resistance tumor.

Targeted co-delivery of resiquimod and a SIRPα variant by liposomes to activate macrophage immune responses for tumor immunotherapy.

Tumor-associated macrophages (TAMs) are the major immune cells infiltrating the tumor microenvironment (TME) and typically exhibit an immunosuppressive M2-like phenotype, which facilitates tumor growth and promotes resistance to immunotherapy. Additionally, tumor cells tend to express high levels of CD47, a "don't eat me" signal, that obstructs macrophage phagocytosis. Consequently, re-educating TAMs in combination with CD47 blockage is promising to trigger intense macrophage immune responses against tumors. As a toll-like receptor 7/8 agonist, resiquimod (R848) possesses the capacity to re-educate TAMs from M2 type to M1 type. We found that intratumoral administration of R848 synergistically improved the antitumor immunotherapeutic effect of CV1 protein (a SIRPα variant with high antagonism to CD47). However, the poor bioavailability and potential toxicity of this combo strategy remain a challenge. Here, a TAMs-targeted liposome (named: R-LS/M/CV1) co-delivering R848 and CV1 protein was constructed via decorating mannose on the liposomal surface. R-LS/M/CV1 exhibited high abilities of targeting, re-education and pro-phagocytosis of tumor cells to M2 macrophages in vitro. Intratumoral administration of R-LS/M/CV1 remarkedly eliminated tumor burden in the MC38 tumor model via repolarization of TAMs to M1 type, pro-phagocytosis of TAMs against tumors, and recruitment of tumor-infiltrating T cells. More encouragingly, due to the double targeting to TAMs and tumor cells of mannose and CV1 protein, R-LS/M/CV1 effectively accumulated at the tumor site, thereby not only remarkedly inhibiting tumors, but also exerting no hematological and histopathological toxicity when administered systemically. Our integrated strategy based on re-educating TAMs and CD47 blockade provides a promising approach to trigger macrophage immune responses against tumors for immunotherapy.