Synthesis And Application Of New Strategies Of Mitochondira-targeting Drug Delivery Nanomedicine

Four different nanoparticle drug delivery systems based on low-cytotoxicity fluorescent carbon dots, polymeric micelles and PEGylated-nanographene oxide were designed and demonstrated. This thesis is mainly about selected deliver anticancer agents to mitochondria to enhanced the therapy efficacy. The results indicate that the drug delivery systems we prepared show multi-function including fluorescence imaging, photo-controlled releasing, photodynamic therapy, p H-responsive, and mitochondion targeting. The main topics of this thesis are as follows:(1) A mitochondria-targeted and NO-releasing nanosystem as a new approach for cancer treatment was demonstrated. The nanosystem was fabricated by covalently incorporating a NO photo-donor and a mitochondria targeting ligand onto carbon-dots, multi-functionalities(mitochondria-targeting, light-enhanced efficient NO-releasing and cell imaging) were achieved. Upon cellular internalization, the nanosystem could target mitochondria and release NO. It was found that, the targeted NO-releasing system can cause high cytotoxicity towards the cancer cells by specifically damaging their mitochondria; and light irradiation can amplify the cell apoptosis by enhancing NO release. These observations demonstrate that incorporating mitochondria-targeting ligand onto a NO-releasing system can enhance its pro-apoptosis action, thereby providing a new insight for exploiting NO in cancer therapy.(2) A mitochondria-targeted and photoactive NO-releaseing system as an anticancer drug was designed and demondtrated. The nanosystem was fabricated by covalently incorporating a NO photo-donor and a mitochondria targeting ligand onto carbon dots; and accordingly, multi-functionalities(mitochondria-targeting, photoactive NO-releasing and cell imaging) were achieved. Upon cellular internalization, the nanosystem could target mitochondria effectively. The action of the nanosystem on two cancer cell lines was evaluataved, compared to the molecular mitochondria-targeted photoactive NO-releasing system, this nanosystem exhibited similarly pro-apoptosis action(good solubility and cellular image).(3) We demonstrate a dual-targeting(both cellular and subcellular targeting) strategy to enhance the PDT efficacy. A cationic porphyrin derivative(Mito TPP) was synthesized as the mitochondrion-targeting photosensitizer; and the dual-targeting PDT system was then fabricated by encapsulating Mito TPP into the acid-responsive and folic acid(FA)-modified polymer micelles. Under acidic p H, the micelles swell as a result of protonation of tertiary amines and disruption of the nucleobase pairing, thereby causing the release of the photosensitizer. Confocal microscope observation shows that, the dual-targeting and micelle-based PDT system can preferably enter folate receptor(FR)-positive cancer cells; and upon cellular internalization, the Mito TPP molecules are released from the micelles and selectively accumulate in mitochondria. Under the light irradiation, the singlet oxygen generated by the photosensitizer causes the oxidant damage to the mitochondrial and subsequently the apoptosis of the cells as evidenced by the loss of mitochondrial membrane potential. Cell viability assays indicate that dual-targeting micelle-based systems exhibit enhanced cytotoxicity towards FR-positive cells. This study may provide a new approach for effectively enhancing the action of PDT systems.(4) The PDT system has been fabricated via the synthesis of a cationic porphyrin derivative(Mito TPP) and the attachment of it onto the polyethylene glycol(PEG)-functionalized and folic acid-modified nanographene oxide(NGO). For the PDT system, NGO serves as the carrier for Mito TPP and also the quencher for Mito TPP’s fluorescence and singlet oxygen(1O2) generation. Confocal microscope observation shows that, the dual-targeting and NGO-based PDT system could preferably enter folate receptor(FR)-positive cancer cells, and the released Mito TPP molecules can selectively accumulate in mitochondria. Under the light irradiation, the singlet oxygen generated by the released Mito TPP causes the oxidant damage to the mitochondrial and subsequently the apoptosis of the cells as evidenced by the loss of mitochondrial membrane potential. Cell viability assays indicate that dual-targeting nanohybrids exhibit enhanced cytotoxicity towards FR-positive cells. In summary, these mitochondria-targeting drug delivery systems have the effect to enhance the efficacy and may provide new approaches for effectively enhancing the action of anticancer systems.