Exosomes as carriers of cancer therapeutics

点击翻译按钮获取中文摘要

Effective treatment of lung cancer remains a formidable clinical challenge. The advent of molecularly- targeted therapies and immune checkpoint inhibitors has shown promise in lung cancer treatment. However, only a subset of lung cancer patients benefit from these therapies. Further, inefficient delivery and accumulation of anticancer drugs in tumor depots combined with dose-limiting toxicity contributes to disease relapse, drug resistance, and metastasis culminating in patient death. As a result, the overall survival rate of lung cancer patients is <16%. Thus, testing of new therapeutics and novel drug delivery systems that can efficiently transport anticancer drugs to tumor depots and kill cancer cells are necessary for improving treatment outcomes. In the present application, we propose testing “exosomes” as drug carriers for cancer therapy. The exosomes derived from normal human lung fibroblast and murine fibroblast cell-derived exosomes (Exo) are loaded with iron-oxide nanoparticles (IONP) carrying an anticancer drug [Doxorubicin (Dox), Cisplatin (CDDP)]. The release of the chemodrug from the IONP is controlled by a pH responsive linker thereby minimizing drug- related toxicity to normal cells. Further, the drug-IONP loaded exosome is decorated with a tumor-targeted ligand for enhancing tumor-specific drug delivery and reducing cytotoxicity to normal cells. Finally, inclusion of IONP enables monitoring tumor growth and treatment response by magnetic resonance imaging (MRI). Pilot studies demonstrated exosomes could be successfully loaded with Dox-, and CDDP-conjugated IONP. Further, excellent drug loading efficiency and drug release kinetics was demonstrated from the exosomes. In vitro studies showed chemodrug-loaded exosomes exerted significant cytotoxicity towards cancer cells but not normal cells. MRI and SQUID studies showed drug-loaded exosomes provided good contrast image without losing the superparamagnetic properties of IONP. Furthermore, tumor-targeted (tt) exosomes directed towards transferrin receptor (TfR) overexpressing lung cancer cells exhibited greater cytotoxicity compared to non- targeted exosomes and accumulated in the tumor xenograft resulting in in vivo efficacy. Based on our compelling preliminary data, we hypothesize that tt-exosomes will efficiently deliver chemotherapeutics to tumor cells and concurrently enable measurement of treatment response by MRI with minimal toxicity to normal cell when tested both, in vitro and in vivo. We will conduct the proposed studies under the following two specific aims. Aim 1a. Physico-biological characterization of tt-exosome as drug carriers for use in in vitro and in vivo studies. Aim 1b. Determine the efficacy of tt-exosome against human and mouse lung cancer and normal cells, spheroids and organoids in vitro. Aim 2. Investigate the in vivo antitumor activity of tt-exosome against lung tumor models.