Computer Simulations To Investigate PH-sensitive Polymeric Micelles Self-assembled From Triblock Copolymers For Anticancer Drug Delivery

Medication is one of the most important means to treat cancer presently. Many drugs for cancer therapies have high activity in vitro, but their applications in the clinic were widely obstructed because of inferior water-solubility, low bioavailability and serious side effects, etc.Therefore, in order to overcome these shortcomings of hydrophobic anticancer drugs in the treatment, the development of the effective drug delivery systems becomes an urgent need to be addressed. Polymeric micelles formed from amphiphilic polymer by self-assembling in aqueous solution which have core-shell structure are a new potential delivery system for anticancer drugs because of their excellent properties such as good stability, high drug loading capacity, small particle size, low toxicity, etc. In this work, doxorubicin(DOX) is selected as the model drug,whereas docosahexaenoic acid(DHA) conjugated Hisx Lysx(DHA-Hisx Lysx) as the drug carrier.The multi-scale simulation, experiment test and theory analysis are utilized to research the crucial questions such as polymer molecular structure, the relation between the meso structure and the properties of micelles, regulation of structures of micelles. These researches can provide valuable guidance for the design and application of the novel drug delivery systems.Dissipative particle dynamics(DPD) was performed to study the aggregate mechanism and microstructure of DOX-loaded polymeric micelles. The effects of the drug content and the water content on the aggregate morphology of DOX-loaded polymeric micelles were investigated. The formation mechanism of drug-loaded polymeric micelles is proposed based on the simulation results. Herein, the formation of DOX-loaded micelles undergoes four stages:(I) Highly dispersed phase;(II) Aggregation of drug and polymer molecules forming clusters;(III)Aggregation of clusters forming small micelles;(IV) Aggregation of small micelles forming stabilized drug-loaded micelles. Under different com-positions of drug and water, the spherical,columnar, and lamellar structures have been observed.Histidine residues in the DHA-Hisx Lysx triblock copolymers are pH responsive blocks,which are hydrophobic segments at pH>6.0 and are hydrophilic segments. So, the pH-sensitive micelles self-assembled from DHA-Hisx Lysx can realize the target delivery of anticancer drugs on the basis of the pH difference between inside and outside of celles. The relationship between structure and performance of drug(doxorubicin, DOX) loaded micelles self-assembled from triblock polymers DHA-Hisx Lys10(x=0, 5, 10) was investigated using experimental research and mesoscale simulation. DPD simulation and experimental results showed that the conformation of micelles and the DOX distribution in micelles were obviously influenced by pH values and the length of the histidine segment. At pH > 6.0, the micelles self-assembled from the polymers were dense and compact and the particle size increased with the increase of histidine length. the micelles from the polymers with histidine residues shows a structural transformation from dense to swollen conformation, leading to an increased particle size from 10.3 to 14.5 DPD units for DHD-His10Lys10 micelles. This structural transformation of micelles can facilitate the release of DOX from micelles at lower pH conditions. The in vitro drug release from micelles is significantly accelerated by decreasing pH value from 7.4 to 5.0, which is consistent with thesimulation results.The compatibility of amphiphilic pH-sensitive polymer(DHA-Hisx Lys10, x=5, 10, 15, 20)and hydrophobic drug(doxorubin, DOX) was reviewed by using multi-scale simulations(DPD simulation and Blends simulation) at different pH conditions, which is in favor of designing and optimizing polymeric micelles as desired drug carriers. The multi-scale simulation results showed that when the chain length of histidine is from 10 to 15 and pH > 6.0, the compatibility between DOX and histidine was better. While the conclusion also indicated that the polymeric micelles self-assembled from DHA-Hisx Lys10(x=10-15) as the ideal carrier for DOX molecules had high drug-loading content and excellent stability which was conducive to improve the utilization of drugs and efficacy of therapy.