Synthesis Of PH-Responsive Metallo-supramolecular Nanogels For Antitumor Drug Deliveries

Cancer has overtaken heart disease and became the leading cause of death worldwide. In order to get desirable anticancer efficacy, drug delivery systems have became the hottest research topic. In the past several years, they have developed into smart drug delivery systems with targeting and simulus-responsive from simple amphiphilic polyer. Recently, the development of supramolecular chemistry provides a potential window to construct smart delivery for anticancer. Supramolecular chemistry acts an important role in natural systems. Learning from nature, a series of p H sensitive drug deliveries were designed and prepared for anticancer delivery. Details were listed in Following:(1)The micelles based on histidine modified dextran-g-cholesterol(HDC) were successfully prepared, which exhibited excellent p H-responsive behavior in acidic aqueous solution(p H<6, within the range of malignant cellular endosome). Taking advantage of this p H-sensitivity in acidic conditions, doxorubicin(DOX), a model anticancer drug, was effectively loaded into the micelles via hydrophobic interactions. The DOX release from all DOX-loaded micelles was accelerated in acid conditions mimicking the endosomal/lysosomal compartments. The enhanced intracellular DOX release was also observed in MCF-7 cells. DOX-loaded p H-sensitive micelles showed higher cellular proliferation inhibition towards MCF-7 cells than that of p H-insensitive micelles. These features suggested that the micelles could efficiently load and deliver DOX into tumor cells, which can enhance the inhibition of cellular proliferation in vitro, providing a powerful mean for delivering and releasing cargoes at the tumor sites.(2) For drug delivery system, the most important factors are biocompatibility and stability. In order to achieve excellent biocompatibility, learning from naturally occurring systems may be the best choice. Herein, a series of p H-sensitive metallo-supramolecular nanogels(MSNs) were prepared by the metallo-supramolecular coordinated interaction between histidine and iron-meso-tetraphenylporphin, which mimicking the way that haemoglobin carries oxygen. With the excellent biocompatibility and special supramolecular p H-sensitivity, MSNs had been exploited to load and release anticancer drug DOX. In vitro drug release profiles showed that only a small amount of the loaded DOX was released in PBS solution at p H 7.4, while there were up to about 80% of the loaded DOX could be quickly released at p H 5.3 due to the p H-depended disassembly of MSNs. CLSM and flow cytometry were used to verify the cellular uptake and intracellular drug release behaviors of DOX-loaded MSNs towards MCF-7. Efficient cellular proliferation inhibition against MCF-7 and He La cells were also observed by a MTT assay. These features suggested that MSNs could be of great potential as intelligent drug delivery.(3) Benefited from the high orientation of coordinated interaction, metallo-supramolecular materials have attracted enormous interests in many fields. Herein, a novel metallo-supramolecular nanogel(MSN)-based drug delivery system for synergistic chemo-photodynamic therapy is explored to enhance anticancer efficacy. It is fabricated by the metallo-supramolecular-coordinated interaction between tetraphenylporphyrin zinc(Zn-Por) and histidine. It can respond to tumor acid microenvironment to release the co-delivered anticancer drug and photosensitizer to kill the lesion cells. Zn-Por moieties in MSN keep the photosensitivity in the range of visible wavelength and possess the ability of generating active oxygen species for photodynamic therapy. The drug-loaded MSN provides a di-functional platform for chemotherapy and photodynamic therapy. Compared with the single chemotherapy of free DOX or photodynamic therapy of Zn-Por in MSN, DOX-loaded MSN with irradiation shows higher in vitro cytotoxicity and in vivo anticancer therapeutic activity, endowing the MSN with great potential for cancer treatments.