Yuxiang Tang,WeiQi Yao,Hang Hu,Wei Xiong,Heng Mei,Yu Hu
TGF-β is widely existed in tumor microenvironment, taking part in tumorigenesis process including angiogenesis, cancer associated fibroblast (CAF) proliferation, and immunosuppression. It inhibited the activation, proliferation, migration and differentiation of T cells, in which way caused a limited therapeutic effects of chimeric antigen receptor T (CAR-T) towards solid tumor such as lymphoma. To targeted block TGF-β at tumor site, we take advantages of nano-techniques to deliver TGF-β inhibitors LY2157299 (LY) towards the tumor sites, in order to help achieve a improved and long-term functions of CAR-T towards lymphoma. Based on amphipathic hydroxyethyl starch-polycaprolactone (HES-PCL), LY and photosensitizer indocyanine green (ICG) were co-loaded in HES-PCL to achieve LY/ [email protected] nanoparticle. The enhanced function of CAR-T benefited from LY/ [email protected] were verified through lymphoma Raji cells in vitro and Nod scid gamma mice engrafted with the Raji cells in vivo. LY was targeted transported to tumor site and accelerated release by mild ICG photothermal. Chemokines CXCL9/10/11 at the tumor site relevant to CAR-T migration and chemokines receptor CXCR3 of CAR-T could be up-regulated by LY, thus facilitated the enhanced accumulation of CAR-T at lymphoma site. T effector memory cells differentiation could also be accelerated by LY/ [email protected] Combined therapy of LY/ [email protected] and CAR-T achieved 2.4 times higher antitumor activity and 2.7 times higher relapse inhibiting rates than CAR-T alone within 15 days and 11 days, respectively. The results suggested that LY/ [email protected] facilitated the enhanced therapeutic index of CAR-T cells towards lymphoma simply and safely, it may be further potentiated applied for other solid tumors.
Jitang Chen,Si Li,Xin Liu,Sha Liu,Chen Xiao,Zhijie Zhang,Shiyou Li,Zifu Li,Xiangliang Yang
Photodynamic therapy (PDT) is frequently used in cancer treatment in clinical settings. However, its applications in stroma-rich solid tumors, e.g., triple negative breast cancer, are limited by abnormal mechanical microenvironments. Solid stress accumulated in stroma-rich solid tumors compresses tumor blood vessels, hampers the delivery of photosensitizers (PSs) in tumor tissues, and poses a major challenge for potent PDT. Here, we report a novel combination strategy to augment PDT based cancer therapy by combining hydroxyethyl starch–chlorin e6 conjugate self-assembled nanoparticles (HES–Ce6 NPs) with the transforming growth factor-β (TGFβ) inhibitor LY2157299 (LY). HES–Ce6 conjugates, as synthesized by one step esterification reaction, could self-assemble into uniform HES–Ce6 NPs, which exhibited enhanced photostability and generated more reactive oxygen species (ROS) under 660 nm laser irradiation than free Ce6. Prior to PDT, intragastric administration of LY decreased collagen deposition, alleviated solid stress, and decompressed tumor blood vessels. As a result, the reconstructed tumor mechanical microenvironment promoted accumulation and penetration of HES–Ce6 NPs into tumor tissues, contributing to augmented antitumor efficacy of HES–Ce6 NP mediated PDT. Modulating tumor mechanical microenvironments using TGFβ blockade to enhance the delivery of PSs in tumors with excessive extracellular matrix represents an efficient strategy for treating stroma-rich solid tumors.
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