Nanoscale Drug Mineralization For Cancer Therapy

Malignancy is one of the most serious threats to human health and chemotherapy is an important treatment in clinical practices. Unfortunately, the chemotherapeutic effects are greatly limited by drug resistances and poor tumor targetings. Recently, scientists have developed various nano delivery systems to enhance drug activity and targeting. However, it is still a challenge for further applications of these artificial nanomaterials due to the biosecurity problems. As the poor biocompatibility, the synthetic nanomaterials are always recognized and quickly cleared by biological systems. Furthermore, a nonspecific accumulation of these materials in vivo would induce undesired side effects.In nature, living organisms can spontaneously produce various nanocomposites to construct functional structures. For example, vertebrates generate nanometer-sized calcium phosphate crystals in the collagen matrix, which can be used to assemble hierarchical bone and enamel. Different from artificial materials, the biosynthetic nanomaterials have excellent biocompatibility and bio-stability. Inspired by natural biomineralization, we combine the antitumor drug and biomineralization to produce biomimetic drug-mineral nanocomplexes. By using such a strategy, we successfully enhance the activities and selectivity of cisplatin and epirubicin. We suggest that biomimetic mineralization is a simple but effect pathway in improving cancer therapy by nanotechnology. The present dissertation has six chapters as followings:Chapter1provides an overview about cancer chemotherapy and biomineralization. We introduce two major problems in current cancer therapy: resistance and selectivity. The development and application of nanotechnology in cancer therapy are subsequently reviewed. In order to avoid the disadvantages that limit clinical application of the current nanosystems, we propose biomineralization-based drug solidification and show the objectives of this study.Chapter2focuses on an in situ mineralization modification of cisplatin and its in vitro and in vivo effect on drug resistance reversion. Free cisplatin is delivered into cells by the copper transport protein (Ctrl) on the cell membrane and the deletion of Ctrl has been proven to be a vital factor for cisplatin resistance. Fortunately, the biomineralized cisplatin nanoparticles adopt an alternative internalization pathway, endocytosis, to bypass Ctrl. The results show that the biomineralization modification can enhance the anti-tumor activities of cisplatin to a level of that of sensitive cells.Chapter3concentrates on the size effect of biomineralized cisplatin particles. We prepare the biomineralized cisplatin nanoparticles with size distributions of50,100, and200nm. These particles have different biodistribution behaviors and therapeutic effect in vitro and in vivo. The study indicates that50nm sized biomineralized cisplatin particles always exhibit the most preferable tumor accumulation with the longest circulation time, demonstrating their potentials in the improvement of current chemotherapy that puzzled by poor selectivity and side effects.Chapter4shows the overcoming of sophisticated multiple drug resistance (MDR) by using biomineralization. Taking EPI (epirubicin) as a model anticancer agent, we developed a one-pot solution mineralization strategy to encapsulate the drug and pooled siRNAs (Pgp and Bcl-2siRNAs) in calcium phosphate (CaP). The resulted EPI-siRNA-CaP naocomplexes can achieve a synergistic effect to full-scalely overcome sophisticated multiple drug resistance by simultaneous inhibitions of drug efflux and intracellular anti-apoptotic defense to maximize the therapeutic efficacy.In Chapter5, we try to combine epirubicin and superparamagnetic iron oxide nanoparticles (SPION) to develop transdermal delivery strategy. In order to circumvent the skin barrier, EPI is attached to SPION to form EPI-SPION nanocomplex, which is a potential drug delivery vector that can be employed for magnetic targeting chemotherapy. Toxicity test revealed that EPI-SPION could inhibit proliferation of skin-melanoma WM266cell, and in vitro transdermal studies demonstrate that the composites can penetrate deep inside the skin driven by an external magnetic field via follicular pathways, implying the great potentials for in situ chemotherapy for skin tumors. Chapter6summarizes the study, which clearly demonstrates that the biomineralization strategy can be successfully applied in improving chemotherapy by overcoming drug resistant and enhancing targeting. This novel strategy is featured by feasible, biocompatible, bio-stable and high effective, which make it more readily for clinical development. We believe that the biomineralization-base nano modification of drugs would hold a promise for effective treatment of various cancers.