Nanomedicine For Gene Delivery And Tumor Photothermal Treatment

Tumor poses a major threat to human health. Traditional treatments, mostly chemotherapy and radiotherapy, offer limited therapeutic efficacy due to their severe side effects. To effectively ablate tumors without damaging normal tissues, innovative treatment modalities have been developed, among which are gene therapy and photothermal therapy. However, current nanosystems for gene delivery or photothermal therapy await further improvement to refine their therapeutic efficacy. For example, gene carriers generally suffer from unstability in vivo, while photothermal nanoparticles normally have limited tumor accumulations. In this dissertation, we focus on(1) enhancing the stability and in vivo transfection efficiency of polyplex-based gene carriers via self-crosslinking of disulfide and (2) constructing novel photothermal nanosystems for better treatment efficacy.(1) Gene carriers with better in vivo stability:Disulfide-exchange cross-links the polyplex of disulfide-containing poly(amido amine) and pDNA upon heating the polyplex solution for a short period. The cross-linked polyplexes based on disulfide-containing poly (amido amine) have excellent stability under physiological salt conditions, and have signifi cantly enhanced transfection activity in the serum media compared to non-cross-linked polyplexes. In vivo, ICR mice were injected with the polyplex through the tail vein, the results show that the transfection efficiency of the cross-linked polyplex is higher than that of the non-cross-linked variety. We have prepared a self-cross-linking PEG-based branched polymer, which easily forms a bioreducible nanoshell around polyplexes of cationic polymer and DNA, simply via heating the polyplex dispersions in the presence of this self-cross-linking branched polymer. This nanoshell can prevent the polyplex from dissociation and aggregation in physiological fluids without inhibiting the electrostatic interactions between the polymer and DNA. Furthermore, glutathione (GSH) can act as a stimulus to open the nanoshell after it has entered the cell. The polyplexes coated with the bioreducible nanoshell show an obvious enhancement in gene transfection in vivo compared with bare polyplexes.(2) Photothermal Nanosystems for better therapeutic efficacy:We constructed three photothermal systems based on two different photothermal agents, the inorganic gold nanocage (AuNC) and the organic polydopamine nanosphere. (1) Short systemic circulation of AuNCs including the PEGylated ones limits their tumor uptake and in vivo tumor treatment efficacy. By cloaking AuNCs with red blood cell (RBC) membranes, a natural stealth coating, we obtained RBC-AuNC nanoparticle that has both the advantages of long circulation from RBC membranes and photothermal effects of AuNC, leading to improved photothermal treatment efficacy as demonstrated in mouse models. (2) Nonleathal thermal treatment makes survivor cells both thermal-and drug-resistant. How to ablate tumors without using skin-harmfully high laser irradiance remains an ongoing challenge for photothermal therapy. By grafting a cationic mammalian-membrane-disruptive peptide, cTL, onto AuNC via Au-S bond followed by co-grafting with thiolated PEG, we obtain a cooperative nanosystem in which AuNC and cTL act as photothermal antenna and anticancer agent, respectively. Upon NIR irradiation at skin-permissible dosage, the resulting cTL/PEG-AuNC nanoparticle effectively ablates both irradiated and nonirradiated cancer cells and effectively destroys tumors without damaging skin tissues thereon as demonstrated in mouse models. (3)How to destroy drug-resistant tumor cells remains an ongoing challenge for cancer treatment. By grafting an acid-activated hemolytic polymer (aHLP) onto photothermal polydopamine (PDA) nanosphere via boronate ester bond, we obtain on a therapeutic nanoparticle, aHLP-PDA, which responsively releases aHLP upon exposure to oxidative stress in tumor microenvironment and/or near-infrared laser irradiation and exhibits stimuli-responsive cytotoxicity to drug-resistant and/or thermo-tolerant cancer cells preferentially at acidic pH over physiological pH, leading to significantly improved treatment efficacy to drug-resistant tumors as indicated by the 100% survival of tumor-bearing mice even on the 32nd day after photothermal treatment.