| Niclosamide is a clinical antiparasitic drug approved by FDA.It can play a therapeutic role in the treatment of cancer,cardiovascular disease,diabetes and other diseases through inhibition or regulation of Wnt/?-catenin,mTORC1,STAT3,NF-?B and Notch signaling pathways.However,the polymer prodrug technology can increase the water solubility,bioavailability and pharmacokinetic characteristics of hydrophobic drugs.Therefore,it is expected to improve the water solubility and bioavailability of niclosamide through polymer prodrug technology,which is an important research direction for the development of niclosamide.The monomer of niclosamide acrylates and niclosamide methacrylates were synthesized by esterification reaction.Three kinds of water soluble polymer-niclosamide were designed and synthesized by free radical polymerization and the micelles(Nic@mPEG-Nic)were prepared using methoxypoly(ethylene glycol)-niclosamide as carriers.The chemical structure,solubility,drug release and biological activity of the polymer-niclosamide and the drug loaded micelles were studied as well as the solubilization and drug release mechanism.The research results on the poly(methacrylic acid)-niclosamide(PMAN)show that,the molecular weight(Mn)of PMAN was 5318Da,the PDI was 1.19,and the drug loading rate was 6.3%.The solubility of PMAN in water was increased by more than 80,000 times.The PMAN can improve the water solubility and bioavailability of niclosamide.It showed dose-dependent vasorelaxation effect on ratmesenteric arteries with intact or denuded endothelium in phenylephrine(PE)and high K+(KPSS)-induced vasoconstriction models in vitro.The research results on poly(N-(2-hydroxypropyl)methacrylamide)-niclosamide(pHPMA-Nic)show that,the drug loading rate was 6.7%,10.1%,and 17.3%.When the drug loading rate was 6.7%,as the concentration of pHPMA-Nic in water increased,pHPMA-Nic gradually formed a network from a spherical shape through the entanglement of hydrophilic chain segment.The hydrophobic chain segment of niclosamide tends to form a small hydrophobic core uniformly distributed in the network without hydrophobic group agglomeration,which can improve the solubility of niclosamide in water by more than 100,000 times.When the drug loading rate exceeds 10%,the hydrophobic segment of pHPMA-Nic tends to agglomerate,as the concentration of pHPMA-Nic in water increases,eventually leading to polymer precipitation.In addition,pHPMA-Nic has obvious inhibitory effect on tumor cells.The research results on methoxypoly(ethylene glycol)-niclosamide(mPEG-Nic)shows that,mPEG-Nic can increase the solubility of niclosmaide by more than 9000 times,and the solubility of mPEG-Nic in water decreases with the increase of drug loading rate.With the increase of drug loading rate,the micelle size formed by mPEG-Nic increased,and the particle size distribution became uniform,the micelles formed by mPEG-Nic ranged from 25 nm to 400 nm.The in vitro drug release data of mPEG-Nic fit the first-order release model better.The intraperitoneal injection of mPEG-Nic in mice inhibited the activity of STAT3 signaling and inhibited tumor growth in vivo without significant in vivo toxicity.The research results on Nic@mPEG-Nic show that mPEG-Nic can effectively load the monomeric niclosmide.And with the increase of mPEG-Nic dosage,the encapsulation efficiency increased and the drug loading rate decreased.The encapsulation efficiency and the drug loading efficiency were up to 58.2%and 16.6%respectively.With the increase of drug loading efficiency,the micellar particle size became smaller and the particle size distribution became uniform,the particle size range was between 100 nm-350 nm.The data of drug release of Nic@mPEG-Nic micelles conform to the first-order drug release model,and the drug release rate increases with the increase of carrier content.In addition,Nic@mPEG-Nic micelles showed a very obvious inhibitory effect on the activity of HCT-116 cancer cells at 48 h. |
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