Design And Synthesis Of Stimuli-sensitive Hyperbranched Polymers For Drug Delivery

Owing to numerous potential applications in the controlled drug delivery and release,hyperbranched polymers have attracted great attention recently. Hyperbranched polymers havethree-dimensional structures and unique properties that are different from those of linearpolymers. For example, various types of hyperbranched polymers have high therapeutic drugloading property and are capable of releasing a payload at the target site. In addition,hyperbranched polymers are usually prepared by facile one-pot synthesis from specificmonomers with branching potential. Hyperbranched poly (3-ethyl-3-(hydroxymethyl)oxetane)(HBPO) is one kind of hyperbranched ether which has been widely investigated as hydrophobicdrug carrier for its special properties, such as low dispersity, low toxicity, various externalfunctional groups and so on. However, HBPO presents certain drawbacks that influence it indrug delivery performance. For instance, the hydrophilicity and stability of HBPO is poor andthere is no stimuli-sensitivity and targeting release properties in HBPO. So it is crucial to impartdesired functionality to target HBPO with appropriate structures and properties.In this paper, a novel pH-and thermosensitive hyperbranched copolymerHBPO-star-PDMAEMAs-SUC (PS) was synthesized. The composition and morphology ofsynthesized copolymers were investigated by1H NMR, dynamic light scattering, andtransmission electron microscopy. The conjugation with folate amine can be easily achievedthrough N,N-Dicyclohexycarbodiimide and N-hydroxysuccinimide (DCC/NHS) chemistry andthe resultant copolymer PS-FOL showed low toxicity to Hela Cells. The PS exhibited phasetransitions in response to pH and temperature. The pH-and temperature-dependent releaseproperties of the drug-loaded micelles were also investigated using indomethacin (IND) as amodel drug. The IND-loaded micelles displayed a rapid drug release at an alkaline pH and atemperature around LCST.Novel biomimetic hyperbranched copolymers were synthesized by polymerization ofzwitterionic monomer (CBB) on the surface of a hyperbranched poly(3-ethyl-3-(hydroxymethyl)oxetane)(HBPO) core. The composition and morphology of resultant copolymers were investigated by1H NMR, DLS and TEM. The biomimetic hyperbranchedcopolymers showed favorable protein resistant properties and were ultra stable in100%fetalbovine serum (FBS). The loading and release properties of a model drug, indomethacin (IND),using the resultant biomimetic hyperbranched copolymers as carriers were also investigated. Theloading content was determined by UV-vis analysis to be22.68wt%and the drug release ratedepends greatly on the pH and protein concentration of the solution. The conjugation withbiomolecules (folate amine) and dye molecules (rhodamine B amine) can be easily achievedthrough DCC/NHS chemistry. The specific cellular uptake of HBPO-PCB-RB micelles wasconfirmed by using fluorescence microscope. To study the feasibility of HBPO-PCB micelles asa potential nanocarrier for targeted drug delivery, we encapsulated a hydrophobic anticancer drug,doxorubicin (DOX), in the hydrophobic core, and the loading content was determined by UV-visanalysis to be5.58wt%. The in vitro cellular cytotoxicity indicated that the HBPO-PCB andHBPO-PCB-FOL micelles (without DOX) had good biocompatibility with Hela cells. TheDOX-loaded HBPO-PCB-FOL micelles show higher cellular proliferation inhibition againstHeLa cells than DOX-loaded HBPO-PCB. These results clearly showed that the biomimeticcopolymer could be as candidate carriers for biomedical applications.