Preparation And Surface-functionalization Of Carrier-free High Drug-loading Content Drug Nanocrystals And Their Applications In Cancer Therapy

Cancer remains one of the most devastating diseases; effective treatment of cancer can alleviate the suffering, improve quality of life and reduce mortality of patients. Chemotherapy has become an integral component of most cancer treatments. Despite the extensive advancements in anticancer research, most anticancer drugs have poor water solubility, limited stability, rapid blood clearance and lack of selectivity, which result in severe side effects and toxicity to healthy tissues. The development of better drug delivery systems for cancer therapy is crucial.Recent development of nanotechnology has led to the exploitation of a variety of nanosized materials for use as drug carriers. Drugs embedded in nanocarriers have been shown to possess obvious therapeutic advantages over ’free’ drugs, which can effectively enhance water solubility and bioavailability of hydrophobic drugs, prolonging the circulation time, preferential accumulation selectively at the tumor sites by the enhanced permeability and retention (EPR) effect. Despite the remarkable merits of drug carriers, there still exist a number of serious problems associated with drug carriers. First is low drug loading capacity, as the carriers are usually the major part with weight far bigger than the drugs (generally less than10%); Second is the possible systemic toxicity from carriers and their biodegradation problems. The drug carriers are typically inert, acting only as the vehicles, but their presence would increase the systemic toxicity of drug formulation, and their subsequent degradation could pose a potential problem, which would impose an extra burden for the patients. Therefore, development of alternative delivery strategies with minimum use of inert materials is highly desirable. To overcome these problems, this thesis is mainly focused on the preparation and application of carrier-free high drug-loading drug nanocrystals for cancer therapy. The shape effect of nanodrugs on the efficencies of cancer therapy was also studies. Moreover, we have also developed core-shell composite drug nanoparticles for thermo-chemotherapy synergistic treatment of cancers. The main results are listed as below:1. We have demonstrated a simple strategy of preparation of carrier-free hydrophobic pure drug nanoparticles (NPs) for drug delivery. As a proof of concept, HCPT NPs with a diameter of about90nm were prepared and then followed by surface modification with amphipathic surfactant through hydrophobic interactions for water dispersity and bio-environmental stability. Significantly, HCPT NPs are aslo readily conjugated with targeting agents to afford a targeted drug delivery system, which exhibit significantly enhanced drug efficacy to specific receptor-positive cancer cells with high selectivity. In vivo studies also show that HCPT NPs possesses obviously superior antitumor efficacy over free HCPT in the excipient mixture at the equivalent dose, and no statistically significant weight loss was observed. This strategy can be generally extended to other hydrophobic drugs to achieve drug nanoparticles for efficient drug delivery.2. We designed two shaped HCPT NCs (NSs and NRs) with similar hydrodynamic sizes and surface charges at a constant chemical composition. Then shape effect of HCPT NCs on cellular internalizing efficiency, in vitro and in vivo anticancer activities was systematically investigated. It was found that HCPT NRs can increase the abundance and rate of cellular uptake of drugs and much higher anticancer efficacy than that of NSs. In vivo studies also show that HCPT NRs possesses obviously superior antitumor efficacy over HCPT NSs and free HCPT in the excipient mixture at the equivalent dose, and no statistically significant weight loss was observed. Our study clearly indicates that the drug NCs shape is an important parameter that must be considered in the design of more effective nanomedicines.3. HCPT NPs@Au (termed GNPs) composite nanoparticles with core-shell structures were prepared by reducing Au nanoparticles onto the surface of HCPT nanoparticles. The as-prepared GNPs were then functionalized by PEG through gold-thiol bonds (termed pGNPs) to improve their water dispersity and bio-environmental stability. UV/vis/NIR spectra of pGNPs displayed an NIR optical absorption peak and could be used as effective thermal generators for photothermo-therapy. The in vitro anticancer efficacy of thermo-chemotherapy therapy was determined to be higher than the chemo-and photothermal therapy alone. In addition, pGNPs exhibited a stealth-like behavior after intravenous injection with a long blood circulation half-life. As a result, an extremely high in vivo tumor uptake of pGNPs attributed to the tumor-enhanced permeability and retention effect was observed. The combined HCPT and photothermal treatment resulted in complete destruction of the tumors without weight loss or recurrence of tumors, while the chemotherapy with the same dose of HCPT or the photothermal treatment without HCPT didn’t. These results demonstrate that chemo-photothermal treatments based on pGNPs are superior to themotherapy or photothermal treatment alone.In summary, the as-prepared carrier-free anticancer drug nanocrystal based delivery systems exhibited enhanced efficacy than the conventional drug delivery systems, which may provide some useful insights and alternative approachs for future research and development of new drug delivery systems. Moreover, our results can serve as guides in the design of new drug nanostructures with significantly enhanced drug delivery outcomes for clinical applications.