Photoresponsive nanomedicines for cancer stemness-targeted combination therapy

Abstract

Cancer stem-like cells (CSCs) make up a small population of solid tumor while they are decisive factors in intratumor heterogeneity, which largely contributes to the resistance to conventional therapy. The self-renewal, high tumorigenicity and invasiveness of CSCs further advance tumor growth and recurrence, leading to poor prognosis of cancer patients. The combination therapy with cancer stemness inhibition is a promising approach for treating a variety of malignancies. However, the random biodistribution of drug molecules will lead to systemic sides effects. Photoresponsive nanoparticle emerges as a validated toolbox to deliver therapeutics with high specificity and efficiency. Through adjusting light irradiation parameters like power density, time and space, the drug molecules can be precisely released at disease lesions according to needs. Moreover, the good stability of drug delivery systems can prolong blood circulation and improve pharmacokinetic profiles of free drug molecules. The minimal leakage of drug molecules in dark environment reduces their cytotoxicity toward normal tissues. In the thesis, the aim is to develop photoresponsive nanoparticles to co-deliver cancer stemness inhibitors and other therapeutics to concurrently combat solid tumor with high efficiency and less side effects. Three combination therapy were proposed and corresponding photoresponsive nanoparticles were fabricated. Gamma-secretase inhibitor was chosen as an anti-cancer stemness agent due to its potent function in deactivating Notch pathway, which is one of three major pathways that regulate CSCs, tumor growth, metastasis, etc. In the first project, a simple yet effective nanoparticle self-assembled from photosensitizer chlorin e6 (Ce6) and gamma-secretase inhibitor MK-0752 was developed. The nanoparticle exhibited enhanced retention in colorectal tumors. Moreover, efficient Notch pathway deactivation sensitized CSCs to photodynamic therapy (PDT), resulting in effective tumor repression. In the second study, a near-infrared (NIR) light-responsive nanocarrier was developed by assembling polyamidoamine (PAMAM) dendrimers modified with photocleavable BODIPY molecules. Chemotherapy drug paclitaxel (PTX) and gamma-secretase inhibitor LY-411,575 were co-loaded for combination therapy. NIR light irradiation could initiate the cleavage and removal of BODIPY molecules, triggering the dissociation of nanocarriers and drug release. The system displayed an excellent anti-tumor efficacy in an orthotopic breast cancer model and effectively repressed tumor recurrence in a post-surgical tumor recurrence model. In the third strategy, a dual-light responsive drug delivery system was designed. Compared with single light, dual-light responsive drug delivery system excels in its ability to control biological functions of different drug molecules with separate irradiation condition. A light-activatable prodrug was synthesized by modifying gamma-secretase inhibitor MK-0752 with BODIPY molecule, which could self-assemble with photothermal agent indocyanine green (ICG) into nanoparticles. This system exhibited 656 nm light-induced drug release and 808 nm light-triggered hyperthermia in vitro. Animal studies verified that the system effectively repressed tumor growth and inhibited tumorigenicity under sequential dual light irradiations. To conclude, three photoresponsive nanoparticles were designed in this project, showcasing great potential in treating multiple malignancies. Further research will be focused on in-deep mechanism study of combination therapy and development of high-tech light delivery techniques to facilitate further clinical translation.