Synthesis Of β-Cyclodextrin Polyrotaxanes、Drug Loading And Their Anticancer Efficacy Study

Cyclodextrins (CDs) are a kind of cyclic oligosaccharides that are made up of sugar molecules bound together in a ring through a-1,4glycosidic bond, have good biocompatibility and biodegradability, and are one of the important host molecules in supermolecular chemistry. CDs can be threaded onto a proper linear polymer molecule under the driving of hydrophobic interaction, hydrogen bond and Van der Waals force, forming polypseudorotaxane (PPR). Polyrotaxane (PR) can then be obtained by capping the PPR with bulky end-caps. Due to the unique structure, good biocompatibility, facile functionalization of PRs and the mobility of CD rings on the polymer axle, the PRs are promising in drug delivery. However, up to now, few studies on PRs used as drug carriers have been reported and mainly focused on in vitro properties. We still know little about their in vivo behaviors such as pharmacokinetics, biodistributions and diffusibility in tumor matrix etc. In addition, most of the published work on PRs is based on a-CD, and the PRs based on β-CD that is widely used and low costs are seldom involved.Herein, we present the preparations of β-CD PRs and the influence of molecular size of PRs on their biological properties.(1) We synthesized β-CD PRs with PPG terminated by alkynyl groups as axle and mono-(6-azido-6-deoxy)-β-cyclodextrin as end-capping group and characterized the PRs with NMR and HR-TEM techniques. The molecular size of the PR was determined to be about2.0nm by HR-TEM.(2) The surface of polyrotaxane was modified with2,2’-(Ethylenedioxy)diethylamine, and a soluble polyrotaxane was then obtained. Thereafter, a succinate-based paclitaxel (PTX) ester derivative was attached to the PRs covalently via amidation. The obtained PR-PTX conjugates had a desirable drug loading content of about29%and the PTX release could be remarkably accelerated by the catalysis of esterase. The in vitro experiments demonstrated that the PR-PTX conjugates could be internalized readily by tumor cells and remain the pharmacological activity of PTX. The investigations of biodistribution, penetration in tumor and antitumor performance revealed that the PR-PTX conjugates could significantly accumulate in tumor with maximum concentration of～3.2%injected dose per gram of wet tissue and penetrate deep in tumor matrix. Thanks to these two aspects, the PR-PTX conjugates exhibit significantly improved antitumor effect comparing to the commercial PTX injection Taxol.(3) Another two batches of β-CD PRs were synthesized by using polymer axles with molecular weight of4kDa and6kDa respectively through the same synthesis route. Their molecular sizes are determined to be4.0and5.9nm by using HR-TEM. The biological properties of all the three batches of PRs were compared, revealing that the larger PRs can be internalized by tumor cells more easily, while the smaller PRs can accumulate in tumor more easily via EPR effect.