| Chemotherapy is the usually used modality for cancer treatment. Polymeric drug nanocarriers have demonstrated to be effective for the improvement of chemotherapy efficacy. Along with the advance of the molecular biology and nanotechnology, gene therapy shows great potential to be another powerful tool for cancer treatment. Recently, acquirement of synthetic gene vehicles with high transfection efficiency and acceptable biocompatibility appears to be the major challenge in the development of gene therapy. Interest in stimuli-responsive polymers is steadily gaining increasing momentum especially in the fields of controlled drug delivery and gene therapy. The stimuli-responsive polymeric nanoparticles have been fabricated based on numerous nanostructures, including micelles, vesicles and hybrid nanoparticles. The changes in chemical or physical properties of polymeric nanoparticles that occur in response to single, dual, or multiple stimuli endow these nanoparticles with the ability to retain cargoes during circulation, target the pathological region, and release their cargoes after cell internalization. Poly-therapy is the combination of various treatment methods with different mechanisms to merge their individual advantages and surmount obstacles in the treatment of disease. Co-delivery polymeric carriers are able to load anticancer drug and compress DNA or siRNA to form nanoscale objects, achieving the simultaneous transport of drug and therapeutic gene in the target cells for enhanced treatment effects. The combination of gene therapy and chemotherapy can not only overcome multidrug resistance, but also make excellent performances and synergism.Chapter1reviewed the up-to-date development of polymeric nanocarriers for the controlled gene/drug delivery. In particular, the recent progress of stimuli-responsive polymeric nanocarriers was emphasized.In Chapter2, a linear-hyperbranched block copolymer of methoxyl-poly(ethylene glycol)-hyperbranched polyglycerol-graft-tris(2-aminoethyl)amine (mPEG-HPG-g-TAEA) was prepared with specially designed multiple functions including strong DNA affinity, endosomal buffering and expected serum-tolerance. Based on the transfection in serum-free and serum-conditioned media, the influences of the polymer structures including the degree of polymerization of HPG and TAEA substitution degree were explored. The vectors could mediate efficient in vitro luciferase expression at levels that are comparable with the commercially available LipofectamineTM2000, while being apparently higher than PEI5K. This linear-hyperbranched vector shows promising potential for the application of gene delivery.In Chapter3, a smart drug delivery nanovehicle was constructed via pH-sensitive assembly pathway for improved cellular internalization and intracellular drug liberation. Through spontaneous formation of boronate linkage in the physiologically normal condition, phenylboronic acid modified cholesterol was able to attach onto catechol-pending monomethoxy poly(ethylene glycol)-poly(L-lysine). This comb-type polymeric assembly could self-organize into micellar nanoconstruction capable of effectively encapsulating poorly water-soluble agents. Triggered by the lysosomal acidity, the structural disassociation of the assemblies is expected to facilitate the intracellular liberation of loaded drugs. Noticeably, cholesterol functionality was specifically incorporated into the nanovehicle structure in order to benefit cellular entry owing to the structural compatibility with the cell membrane.In Chapter4, a pH-responsive drug/gene co-delivery nanoplatform is designed for cancer treatments with the excellently serum-tolerant transfection activity and the capability to load and release hydrophobic drugs in an acidity-accelerated manner. Via boronate linkage, y-CD is allowed to spontaneously attach onto phenylboronic-acid-modified oligoethylenimine (PEI1.8K-PB2.9) at neutral condition. The formed vehicle/DNA nanoformulation is thus surrounded densely by y-CD moieties to biomimic the carbohydrate-rich cell surface, providing a novel approach to overcome serum-susceptible drawbacks frequently associated with synthetic gene carriers. An anticancer drug of doxorubicin (DOX) is shown to be readily accommodated into the nanoformulation via host-guest chemistry and intracellularly co-delivered together with plasmid DNA. Due to the acidity-labile feature of boronate linkage, DOX/y-CD inclusion complexes would be mostly detached from the nanoformulation triggered by acidity, leading to faster drug release. Furthermore, drug inclusion does not alter the serum-compatible transfection efficiency of PEI1.8K-PB2.9-Y-CD.In Chapter5, a supramolecular amphiphile was synthesized through the AD/CD host-guest interaction between adamantane-terminated alkyl chain (C18-AD) and amine-attached ?-cyclodextrin-centered hyperbranched polyglycerol (CD-HPG-TAEA). Just by mixing them together, supramolecular assembly afforded the cationic vesicle in normally physicological condition. Water-soluble DOX-HC1could be loaded into the hollow core of vesicle and the in vitro drug release pattern from vesicle could be controlled by adjusting the environmental pH, which is favorable for the intracellular liberation of entrapped drug caused by the acidic microenvironment in the lysosomal organelle. The formed nanoassembly exhibited better serum-tolerant transfection activity and significantly lower cytotoxicity than PEI25K. It is believed that the novel cationic charged vesicle may hold vast potential for the co-delivery of therapeutic drug and gene.In Chapter6, a module-template strategy was proposed for the construction of low-molecular-weight cationic assemblies for gene transport. Based on specific host-guest interactions between amine-modified ?-cyclodextrin (CD-TAEA) and functional adamantane (AD) derivatives, the strategy offers great flexibility in terms of the introduction of mono-or multi-functionality by the inclusion of one or more adamantane-based modules with the desired functionalities. As proof of concept, phenylboronic acid (PB) containing adamantane (PB-AD) was used as a model module in the hope of offering enhanced cytosolic delivery in consideration of the special affinity of PB groups with cell membranes. Compared to the parent CD-TAEA, PB-AD/CD-TAEA assemblies mediated higher transfection rates. The encouraging results suggest that CD-TAEA can be developed as a powerful template capable of readily accommodating various AD-based modules giving versatile functionalities for improved transfection. |
PDF Full Text Request