Preparation Of High Drug-loading Content Nano-sized Multidrugs With Synergistic Therapeutic Effect And Their Applications In Cancer Therapy

Cancer is one of the most common causes of death in the world, andchemotherapy remains a major base of cancer treatment. The use of a single agentoften fails to achieve complete cancer remission due to the rapid development ofdrug resistance in tumor cells. To overcome these problems and enhance anticancerefficacy, co-delivery of multifunctional agents to achieve synergistic effects andovercome drug resistance is a promising approach, which have received considerableresearch interest in cancer therapy. Nevertheless, the drug loading capacity in thenanocarrier-based delivery systems is rather low, as the carriers are usually the majorpart with weight far bigger than the drugs (generally more than80%). In addition,the drug carriers are typically inert, but their presence and subsequent degradationwould increase the systemic toxicity of drug formulation. Therefore, we havedeveloped co-delivery systems with minimum use of inert materials (high drugloading capacity), enhanced therapeutic efficiency and improved tolerance which ishighly desired in the biomedical field. The main results are listed as below:1. We developed carrier-free multidrug nanocrystals (MDNCs) for thecombination chemotherapy with synergistic effect, improved tolerance and imagingcapability for cancer treatment. Three widely used hydrophobic drugs, methotrexate(MTX),10-hydroxycamptothecin (HCPT) and paclitaxel (PTX), were prepared intoone nanorods, and then conjugated with poly(ethylene glycol)(PEG) to improvetheir water dispersity and bio-environmental stability. It should be noted that onlytrace amount of PEG was used for surface modification, which ensures a high drugloading capacity of the resulting PEGylated MDNCs. In vitro studies showed thatthe MDNCs revealed synergistic effect and improved tolerance. After in vivointravenous injection, the MDNCs exhibits a synergetic in vivo therapeutic effect and possesses obviously superior antitumor effect compared to free multidrugstreatment group and individual drug treatment groups, and no statistically significantweight loss was observed. The MDNCs can also gain imaging capabilities byencapsulated with an organic dye, which render the multidrug nanorod an all-in-oneprocessing system for cancer diagnosis and treatment.2. We have prepared multifunctional pure doxorubicin nanoparticles (DOX NPs)for diagnose and chemotherapy simultaneously. After surface functionalized withPEG–PLGA, DOX-PEG NPs have supernal drug loading capacity (90.47%) andexcellent stability. In vivo studies showed that DOX-PEG NPs exhibited favorableblood circulation time and intense accumulation in tumor area, therefore remarkableperformance of in vivo imaging was also obtained. In addition, in order to overcomethe drug resistance of cancer cells, we doped a number of10-hydroxycamptothecin(HCPT) into DOX NPs. The resulted DOX-HCPT NPs exhibited a powerfulinhibition against drug-resistant cells so as to realize synergistic chemotherapy. Forin vivo anticancer activities, both DOX-HCPT NPs and DOX-HCPT-PEG NPsshowed obvious antitumor efficacy, while health effects in mice could be ignored.