Study On Supramolecular Chemistry Based Nano Drug Delivery Systems

In recent decades, nanomaterials have been more widely used in biomedical field, especially in the fields of cancer therapy and diagnosis. Compared to small molecule anti-cancer drugs, nanomedicines have many advantages such as long blood circulation time, high drug accumulation in tumor sites and low toxicities. Such advantages enable nanomedicine to be very promising in tumor treatment. Some widely used nanocarriers, such as micelles and vesicles, are constructed by amphiphilic polymers. However, the properties of nanomaterials synthesized by traditional covalent chemistry are constrained by the chemical structures of the polymers. Sometimes the synthesis is quite tough or even unable to give the desired product. Furthermore, the materials constructed by covalent chemistry have a relatively fixed structure which makes the functionality of materials severely restricted. In order to overcome these disadvantages, supramolecular chemistry has been more and more employed to prepare the materials for drug delivery. Unlike covalent chemistry, supramolecular chemistry bases on several non-covalent interactions such as H-bond, electric interaction, π-π interaction and van der waals interaction which can be formed under mild condition. The interactions are reversible and sometimes environmental responsible. For these advantages, the nanomaterials constructed by supramolecular chemistry have a more diverse structure and environmental responsive groups are easier to be introduced into the system. These nanocarriers also have better anti-cancer activities.In this thesis, we utilized P-cyclodextrin and phenylboronic acid as building blocks to construct nanocarriers by supramolecular chemistry strategies. In vivo/in vitro biological effects and the in vivo anti-cancer activities of drug loaded nanocarriers are evaluated. The main contents are described as below:(1) By using the 6-OH of P-cyclodextrin,4 and 7 poly(N-vinylpyrrolidone) chains were introduced to P-cyclodextrin successfully. Adamantane terminated linear poly(ε-caprolactone) were also prepared by ring-opening polymerization. Supramolecular micelles can be constructed through the host-guest interaction between β-cyclodextrin and adamantane (PVP-PCL micelles). The properties of the supramolecular micelles such as diameter, morphology, critical micellization concentration (CMC) were characterized.(2) We further evaluated the anti-fouling efficacies and the stabilities of the synthesized PVP-PCL micelles. Cabazitaxel was encapsulated into the micelles and showed great antitumor efficacy in vitro. The micelles also display a certain extent penetrating ability to 3D cells. The studies of biodistribution and in vivo antitumor activities indicated that PVP-PCL micelles have a better antitumor efficacy than free drug and may improve the tumor accumulation of drugs.(3) By introducing phenylboronic acid onto the two hydroxyl groups of 10-hydroxycamptothecin (HCPT), we successfully synthesized a novel HCPT derivative as a crosslinker. A 1,2-diol rich copolymer were prepared and then crosslinked by the HCPT derivative crosslinker to form the nanoparticles. The diameter, morphology and drug loading content were characterized. Further in vitro studies indicated that the HCPT crosslinked nanoparticles have great antitumor activities.(4) By modifying xanthate groups onto two hydroxyl groups of HCPT, we successfully synthesized a chain transfer agent (CTA) based on HCPT. Then RAFT polymerization was employed to conjugate PVP to hydroxyl groups of HCPT and a novel HCPT prodrug was prepared. Then the chemical structure, molecular weight and drug loading content were characterized. The HCPT prodrug may form true solution or micelles in water according to the molecular weight of PVP chains.