Construction Of Smart Nanocarriers For Targeted Delivery And Controlled Release Of Anticancer Drugs

Cancer is a severe threatens to human healthy and survival, which is a main cause of disease leading death. Conventional chemotherapy mainly relies on systemic administration of anticancer drugs, leading to nonspecific drug biodistribution throughout the body and nondifferential killing of both cancerous and healthy tissues/cells. Another obstacle of chemotherapy is hypoxia, which is caused by an inadequate oxygen supply. Hypoxia can be a direct cause of multi-drug resistance (MDR) because some drugs require oxygen to be maximally cytotoxic. MDR, the principal mechanism by which many cancers develop resistance to chemotherapeutic drugs, is a significant challenge in the clinical treatment of cancer.Photodynamic therapy (PDT) has several advantages over conventional therapies because of its noninvasive nature, the fast healing process resulting in little or no scarring, and the ability to treat patients in an outpatient setting. Although PDT has become a promising treatment option for early stage cancer and an adjuvant for surgery in late-stage cancer, its clinical application is still obstacled by tumor hypoxia which severely reduced the therapeutic efficiency due to the 02-dependent nature of PDT. Another obstacle of PDT is the limited tumor selectivity which causes damage to adjacent healthy tissues.To solve the problems in cancer chemotherapy and PDT, nanotechnology combined with life sciences and medicine provides a new platform for cancer diagnosis and therapy. With the emergence of novel nanomaterials and methods, pharmaceutical sciences based on bio-nanotechnology have made great progress. For example, using nanocarriers to selectively delivery drugs and subsequently release the drugs to a diseased region upon stimulation by tumor-specific microenvironments or markers have become an efficient way to improve the therapeutic efficacy. Focusing on the critical problems of poor cancer targeting, multi-drug resistance of the tumor, low selectivity of PDT and the hypoxia-induced poor PDT efficacy in current cancer treatments, this study designs and constructs multifunctional "stimulus-responsive" nanocarriers for controllable release of drugs, achieving highly selective and efficient cancer chemotherapy and PDT. The works of thesis includes the following sections:1. A H2O2-Responsive Nanocarrier for Dual-Release of Platinum Anticancer Drugs and O2:Controlled Release and Enhanced Cytotoxicity against Cisplatin Resistant Cancer CellsSince most tumor cells are under persistent endogenous ROS stress, H2O2 could be useful as a cancer-related stimulus for targeted drug release to diseased tissue. Herein, we report a nanocarrier system which combines catalase and platinum anticancer agents together and synergistically releases both drug molecules and O2 when triggered by biologically relevant concentration of H2O2. In this system, poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) was chosen as drug carrier, because PLGA possesses excellent biocompatibility and has been widely used in drug release system. Catalase was incorporated into the aqueous core of PLGA NPs as an O2-generating agent together with platinum anticancer agents. Catalyzed by catalase, O2 is evolved when intracellular H2O2 penetrates into the NPs, which causes the shell rupture of NPs owing to the increase in internal pressure. As a result, the NPs could selectively unload the encapsulated drugs in virtue of the high levels of ROS stress in cancer cells, resulting in cellular apoptosis. Moreover, the O2 produced in the drugs release process can be helpful for overcoming hypoxia-induced MDR and enhancing the efficiency of cancer chemotherapy.2. An ATP-Responsive Drug Delivery System for Mitochondria-Targeted Controlled Release of Doxorubicin in Cancer CellsA new ATP-responsive nanocarrier for mitochondria-targeted chemotherapy was demonstrated. Adenosine-5’-triphosphate (ATP) as a trigger was utilized for the controlled release of doxorubicin. Dendrigraft poly-L-lysines (DGL), which are novel drug-delivery vehicle, are conjugated to cancer targeting aptamer and mitochondria-specific binding aptamer. We demonstrate that aptamer modified nanocarrier functionalized with an ATP-binding aptamer-incorporated DNA motif can selectively release doxorubicin into mitochondria of cancer cells induced by ATP. The half-maximal inhibitory concentration of ATP-responsive nanovehicles is 1.5 μM in PC3 cells, improving the cytotoxicity compared with that of non-ATP-responsive nanovehicles.3. H2O2-Activatable and O2-Evolving Nanoparticles for Highly Efficient and Selective Photodynamic Therapy against Hypoxic TumorThe low selectivity of the currently available photosensitizers, which causes the treatment-related toxicity and side effects on adjacent normal tissues, is a major limitation for clinical PDT against cancer. Moreover, since PDT process is strongly oxygen dependent, its therapeutic effect is seriously hindered by hypoxia of tumor. To overcome these problems, a cell-specific, H2O2-activatable and O2-evolving PDT nanoparticle (HAOP NP) is developed for highly selective and efficient cancer treatment. The nanoparticle is composed of photosensitizer and catalase in the aqueous core, Black Hole Quencher in the polymeric shell, and functionalized with a targeting ligand. Once the HAOP NP is selectively taken up by αvβ3 integrin-rich tumor cells, the intracellular H2O2 penetrates the nanoparticle and is catalyzed by catalase to generate O2, leading to the shell rupture and release of photosensitizer. Under irradiation, the released photosensitizer induces the formation of cytotoxic singlet oxygen (’02) in the presence of O2 to kill cancer cells. The cell-specific and H2O2-activatable generation of 1O2 specially destroys cancer cells and prevents the damage to normal cells. More significantly, the HAOP NP could continuously generate O2 in PDT process, which greatly improved the PDT efficacy in hypoxic tumor. Therefore, this work presents a new paradigm for H2O2-triggered PDT against cancer and provides a new avenue for overcoming hypoxic conditions to achieve effective treatment of solid tumors.