Study On The Preparation Of Functional Antitumor Drug Loaded Nanomaterials And Anti-cancer Research

Paclitaxel ?PTX?, one of the most common antitumour drugs, has been widely used to treat different kinds of tumors, including breast cancer, advanced ovarian carcinoma and lung cancer, through strengthening the assembly of microtubules from tubule dimers and stablizing them from depolaring. However, its therapeutic outcome in clinic is greatly restricted because of its low water solubility. This problem is currently overcomed by dissolving paclitaxel in a Cremophor EL???/ethanol mixture, which is commercially available as Taxol???. Unfortunately, the presence of organic stablizer, such as ethanol and Cremophor EL???, results in serious side effects like hyper sensitivity reactions, nephrotoxicity and neurotoxicity. Thus, the development of new drug delivery systems which can effectively deliver PTX to tumor and prevent the drug rapidly washout from tumor site is highly desirable.In order to enhance the therapeutic efficacy, the combination of photothermal therapy ?PTT? with chemotherapy is highly desirable due to the synergistic effect. Although the mechanism of heat induced enhancement in cytotoxicity is not completely known, these drugs are expected to be useful to assist PTT therapy which has the obvious temperature raise. On the other hand, combining drug with heating can lower the drug dosage requirements to achieve comparable cytotoxicity of the unheated drug amount, and this has important implications to the dose-dependent side-effect of chemotherapeutic agents. Since traditional chemotherapeutic drugs bring severe side-effects such as liver and kidney toxicity as well as cardiotoxicity, the combined therapy is expected to minimize systemic side-effects of chemotherapeutic agents by lowering the drug doses. Thus, to achieve good therapeutic efficacy and low systemic toxicity, the combined therapy is being actively pursued.It is believed that the characteristics such as size, shape, and surface chemistry affect nanoparticle target within bodies. When the size and shape are fixed, the surface chemistry will play a central role in determining the efficiency and mechanism of cellular uptake, and in vivo fate of nanoparticles. So far, there are a number of strategies to the introduction of PEG or zwitterionic polymers to the surface of nanoparticles to prolong circulation time of nanoparticles in body. However, a comparison study of PEGylated nanopartcles with PCB-and PMPC-decorated nanoparticles has rarely been reported. Thus, it is greatly interesting to investigate the effects of poly?zwitterions?s versus poly?ethylene glycol? surface coatings on the biodistribution of nanoparticles.Based on the above ideas, the detailed work is described as below:?1? A nano-assembled drug-delivery system for anticancer treatment, formed by the host-guest interactions between paclitaxel ?PTX? and ?-cyclodextrin ??-CD? modified poly?acrylic acid? ?PCDAA? was successfully prepared. After such design, the aqueous solubility of PTX was greatly increased from 0.34 ?g/mL to 36.02 ?g/mL, and the obtained PCDAA-PTX nanoparticles ?PCDAA-PTX NPs? exhibited a sustained PTX release behavior in vitro. In vitro cytotoxicity found that PCDAA-PTX NPs could significantly accumulate in tumor cells and remain the pharmacological activity of PTX. The in vivo real-time biodistribution of PCDAA-PTX NPs was investigated using near-infrared fluorescence imaging ?NIRF?, indicating that the PCDAA-PTX NPs could effectively target to the tumor site by the enhanced permeability and retention ?EPR? effect in H22 tumor-bearing mice. Through in vivo antitumor examination, PCDAA-PTX NPs exhibited superior efficacy in impeding the tumor growth compared to the commercially available Taxol???.?2? Based on the electrostatic interaction between positively charged chitosan ?CS? with good biocompatibility and biodegradability and negatively charged W₁₈O₄₉ nanoparticles with excellent photothermal effect, we prepared the CS-WO hydrid nanospheres. And antitumor drug doxorubicin ?DOX? was also loaded into the CS-WO nanoparticles to afford the combination treatment of thermotherapy and chemotheraphy for cancer. The in vitro and in vivo behaviors of the CS-WO-DOX nanoparticles were examined by dynamic light scattering, transmission electron microscopy, cytotoxicity, near-infrared fluorescence imaging, tumor growth inhibition and biodistribution. It was found that by virtue of the synergic effect of W₁₈O₄₉ nanoparticles and DOX, the antitumor ability was significantly improved, resulting in superior efficiency in impeding tumor growth and extension of the life time of mice.?3? Zwitterionic poly?carboxybetaine? ?PCB?, poly?2-methacryloyloxyethyl phosphorylcholine? ?PMPC? and non-ionic polyethylene glycol) ?PEG?, which have similar degrees of polymerization, were grafted to branched polyethyleneimine ?PEI? to generate PCB-grafted PEI ?PEI-PCB?, PMPC-grafted PEI ?PEI-PMPC? and PEG-grafted PEI ?PEI-PEG? copolymers, respectively. These grafted PEI copolymers with almost the same grafting number were coated on the surface of 110 nm bovine serum albumin-poly?N-3-acrylamidophenylboronic acid? ?BSA-PAPBA? nanoparticles to make a comparison of the surface decoration effect on the biodistribution of nanoparticles. Compared to the nanoparticles without surface decoration, surface decoration with the copolymers significantly prolonged the circulation time of BSA-PAPBA nanoparticles, leading to remarkable enhancement of tumor uptake of the nanoparticles. The drug accumulation at the tumor site reached more than 10% injected dose per gram of tumor. Among them, the PEI-PMPC-decorated nanoparticles exhibited the best performance in tumor accumulation and anticancer ability. Thus, these surface-decorated nanoparticles may serve as a strong candidate for high tumor accumulation of drug delivery systems.