Construction And Evaluation Of Hypoxia-responsive Controlled-release Drug Delivery System

Recent years,stimuli-responsive drug delivery systems(DDS)have shown great potential in tumor therapy.Compared with traditional DDS,loaded drug in stimuli-responsive DDS could be selectively released at tumor sites which decreases side effects and improves treatment effectiveness.Hypoxia is a significant property of diverse solid tumors.The feature of high metabolism and rapid proliferation,the formation of abnormal blood vessels in tumor tissues among with some specific treatments could result in tumor hypoxia.Some nitro-derivatives have hypoxia-responsive property.Thus,in this paper we combined hyaluronic acid(HA),mesoporous silica nanoparticles(MSNs)with nitro-derivatives respectively to design two kinds of hypoxia-responsive drug carriers.The study could be divided into the following 3 parts:(1)The preparation and hypoxic response studies of HA-NIH micellesA hypoxia-responsive drug carrier was developed by grafting HA with 2-NIH through amide bond.Three feed ratios were designed and the highest degree of substitution(DS)of HA-NIH conjugates was 6.5%.Under hypoxic condition,Zeta potential of micelles increased to-24.9 mV and the integrity of micelles was destroyed through atomic force microscope(AFM)and transmission electron microscopy(TEM)observation.The highest drug-loading content(DL)and entrapment efficiency(EE)were calculated to be 6.0%,63.8%respectively.(2)The preparation and hypoxic response studies of HA-NIE micellesA hypoxia-responsive drug carrier was developed by grafting HA with 2-NIE.Four feed ratios were designed and the highest DS of HA-NIE conjugates was up to24.2%.Compared with HA-NIH micelles,HA-NIE micelles revealed a faster and more complete response behavior.By adjusting the dosage of DOX from 5%to 20%,corresponding influences on DL and EE of HA-NIE micelles were discussed by UV-Vis analysis.It was found that the highest EE was reached as 84.7%with the addition of 10%DOX.Drug release studies of HA-NIE micelles with different DL revealed that all the micelles could release drug quickly and completely.(3)The preparation and hypoxic response studies of CMSNs-NBCFHypoxia-responsive moiety nitrobenzyl ester was attached on the surface of MSN.?-cyclodextrin(?-CD)was added and employed as a gatekeeper after the drug loading.Modifications of MSNs were confirmed by FT-IR and thermo gravimetric analysis.The size of MSNs was uniform and about 150 nm.After the addition of?-CD,pore parameters of CMSNs-NBCF decreased significantly(specific surface area was 653 m~2/g,specific pore volume was 0.490 cm~3/g).Under hypoxic condition,Zeta potential of CMSNs-NBCF increased from-4.9 mV to 19.7 mV and the drug was released completely.