Construction Of Biomedical Polymer Materials Based On Copper-catalyzed Multicomponent Polymerization Of Alkynes

Multicomponent polymerization(MCP)is a new polymerization method by using three or more monomers to construct target polymers in one-pot.It has the advantages of high atomic economy,mild reaction conditions,easy post-modification and simple operation,and can be used as an efficient synthesis tool to synthesize functional polymers in different fields.Copper-catalyzed multicomponent polymerization of alkynes,as one of the typical multicomponent polymerization,can be used to efficiently synthesize functional polymers at room temperature,and nitrogen as the only byproduct is released.Therefore,such multicomponent polymerization is a green polymerization method.Based on the copper-catalyzed multicomponent polymerization of alkynes,various types of functional monomers are designed to synthesize target functional polymers,which effectively expand the application value of this polymerization method in different fields.In order to develop the applications of the copper-catalyzed multicomponent polymerization of alkynes in biomedical materials field,copper-catalyzed MCPs toward biodegradable polymers with diverse responsiveness in tumor microenvironments were developed using diynes,sulfonyl azides and a series of tumor microenvironments-responsive,cleavable diols.The resulting polymers showed high molecular weights(up to 12000 g/mol)and high yields(up to 96%).The biodegradable polymers displayed excellent degradation performance in various simulated tumor microenvironments.One typical photosensitizer,tetraphenyl porphyrin,was conjugated to the side chains of the polymers by Sonogashira reaction.The poly-porphyrin displayed higher singlet oxygen quantum yield than the porphyrin monomer due to the controlled conjugation efficiency and the unique MCP structure,which provided a complementary strategy to limit the undesired aggregation caused-quenching(ACQ)effect.Then,based on copper-catalyzed three-component polymerization of alkynes,a copper-catalyzed four component polymerization was developed using alkynes,sulfonyl azides,diols and electrophilic reagents.A variation of electrophiles including alkyl glyoxylates,nitroalkenes,and Morita-Baylis-Hillman adducts were selected to successfully synthesize a library ofα-functionalized poly(N-sulfonylimidate)s with a wide substrate scope,as well as high molecular weights(up to 30300 g/mol).Meanwhile,the mechanism of polymerization reaction was studied,proving that the copper-catalyzed four component polymerization was in accordance with the mechanism of stepwise polymerization.A new synthesis strategy was provided for the construction of functional four component polymers.In addition,a dual redox-responsive Se-containing polymer was prepared by using Se-containing diol basing on copper-catalyzed MCP of alkynes.The degradation performance of the polymer was studied by X-ray photoelectron spectroscopy(XPS)and nuclear magnetic resonance spectrometer(NMR)under the redox conditions of simulated tumor microenvironment.It was found that the selenite acid was produced by Se-containing polymer under the oxidation conditions and selenol was formed under the reduction conditions,both of which showed excellent degradation performance.Amphiphilic Se-containing polymers were synthesized using hydrophilic polymer of polyethylene glycol to modify in the polymer side chain.The characterization of the micelles showed that the particle size was about 130 nm,the encapsulation rate of DOX was 63.4%,and the critical micelle concentration(CMC)value was 0.23 mg/m L.Under normal physiological conditions,the nano micelles remained structurally stable.However,in a tumor environment containing reactive oxygen species(ROS)or glutathione(GSH),DOX was released from the drug-loaded micelles,and the cumulative release amount of DOX reached 99%.The main reason for this result was that the diselenide bond in the polymer backbone was cleaved under redox conditions.It was found that nano drug-loaded micelles had better drug release performance in the GSH environment than in the ROS environment.The study has shown that the redox-responsive amphiphilic polymer was conveniently constructed through MCP,and the polymer exhibited specific degradation properties in the tumor microenvironment.This work provided a new idea for the development and design of intelligent nano drug-loaded micelles.Finally,photodynamic therapy(PDT)is showing great potentials in the treatment of cancer diseases and photosensitizer plays crucial roles in absorbing the energy of light and generating ROS during PDT.Most of the photosensitizers bearing macrocyclic structures have strong hydrophobicity and suffer from theπ-πinteraction and undesired aggregation caused quenching,which severely limit the PDT efficacy.Moreover,the continuous oxygen consuming during PDT also leads to the up-regulated expression of hypoxia inducible factor-1α(HIF-1α),which can aggravate the growth of tumors.To overcome the above-mentioned problems,polymerized photosensitizers repelled by flexible linkers were designed and synthesized using multicomponent polymerization(MCP)method to afford the poly-porphyrins with high molecular weight(M_w>20000 g/mol)under room temperature.The ACQ effect could be significantly inhibited by introducing flexible chains and increasing the M_w,leading to the improvement of singlet oxygen quantum yield and photo-toxicity simultaneously.A HIF-1αinhibitor,lificiguat(YC-1)was synthesized as a chemo-drug and co-delivered with poly-porphyrins to decrease the expression of HIF-1αand inhibit the tumor growth under hypoxia.The characterization of the micelles showed that the particle size was nanospheres about 200 nm and the encapsulation rate of photosensitizer was 63.5%.With the synergistic PDT and chemotherapy,poly-porphyrin/YC-1 micelles showed excellent therapeutic anti-tumor efficacy both in vitro and in vivo.A new strategy was provided to treat hypoxia tumor.In summary,copper-catalyzed multicomponent polymerization of alkynes was used to prepare functional polymers,including responsive polymers toward specific tumor microenvironment and poly-photosensitizers,which expanded the applications of the polymerization in biomedical materials.Meanwhile,the copper-catalyzed four component polymerization of alkynes was developed.This new synthetic method offered an efficient way to synthesize the polymers with diverse structures and rich functions.