| At present,cancer has become one of the most serious threats to public life and health.However,the technology of cancer treatment generally brings some unsatisfactory effects,such as the poor targeting of drugs,the drugs will have certain toxic and side effects,and the overall immunity of organisms will be reduced.The effective way for researchers to solve the poor targeting and side effects of anticancer drugs is to prepare drug carriers responsive to environmental stimuli for drug delivery and effective control of drug release.Nano carriers which are sensitive to the micro environmental stimuli(pH,reduction,temperature,electricity,magnetic field and light)in the system have attracted much attention.In this paper,nano drug carriers responsive to environmental stimuli were prepared to study the drug controlled release performance in simulated human physiological microenvironment.In this paper,Tetraethoxysilane(TEOS)and 1,2-Bis(triethoxysilyl)ethane(BTSE)were used as silicon precursor,Cetyltrimethylammonium bromide(CTAB)as template,N-isopropyl acrylamide(NIPAM)as comonomer,Sodium dodecyl sulfate(SDS)was a surfactant,Potassium persulfate(KPS)as initiator,The hybrid mesoporous silica nanospheres(MSNs)with polyacrylic acid(PAA)as the encapsulation material(PAA-PNA-MSNs),PAA and poly(N-isopropylacrylamide)(PNA)as the polymer coating of the hybrid MSNs(PNA-MSNs),and the composite nanospheres with PNA,PAA and chitosan(CTS)as the coating layer of hybrid MSNs(MSNs-CTS-PNA)were prepared,respectively.The drug loading,drug controlled release performance and cell biological evaluation of these three novel dual-sensitivity composite nano-microspheres were studied.The main research contents are as follows:(1)Preparation and modification of MSNs based on two silicon sourceHybrid mesoporous silica nanospheres were synthesized using TEOS and BTSE as silicon source precursors and CTAB as template under mild reaction conditions,high-speed stirring,alkaline catalytic hydrolysis condensation and template removal.Many factors affecting the morphology of MSNs were investigated,such as the acidity and basicity of the reaction system,the amount of template and stirring rate.In order to increase the drug loading,MSNs were treated by hydrothermal method to obtain hollow hybrid MSNs.In order to improve the stability,dispersion and application value of MSNs,organic functional groups were introduced to modify the surface of MSNs.The chemical modification of MSNs with?-(methacryloxy)propyltrimethoxysilane(MPS)was carried out.The results of FTIR,BET and pore size analyzer showed that MPS was modified on MSNs,which would be helpful for the further application of MSNs as nano carriers in drug controlled release research.(2)Preparation and drug controlled release properties of PAA-PNA-MSNsBased on the synthesized MSNs,PAA-PNA-MSNs with pH/temperature dual sensitivity were prepared by using NIPAM as polymerization monomer,KPS as initiator and PAA as encapsulation material.The results showed that PAA-PNA-MSNs/DOX had good temperature sensitivity and pH sensitivity.Dox was used as a drug model to study the drug loading and controlled release behavior of PAA-PNA-MSNs.The experimental results showed that the drug carrier had good temperature and pH sensitivity.The loading efficiency of DOX was(62.4±2.9)%.In vitro cell experiment,PAA-PNA-MSNs blank nano carriers had no cytotoxicity,while PAA-PNA-MSNs/DOX showed good anticancer activity.After 10 hours of cumulative release,the cumulative drug release rates were(72±2)%(pH 7.4),(75±1)%(pH 6.5)and(80±1)%(pH 5.0),and(76±2)%,(81±1)%and(84±3)%at 25 ~oC,37 ~oC and 42 ~oC,respectively.PAA-PNA-MSNs were expected to be potential drug carriers in the field of controlled drug release due to their good biocompatibility,drug controlled release behavior,dual sensitivity to temperature and pH,and good anticancer activity.(3)Preparation and drug controlled release properties of PNA-MSNsBased on the synthesized MSNs,pH/temperature sensitive PNA-MSNs composite nanospheres were prepared using AA and NIPAM as monomers and KPS as initiator.DOX was used as a model drug to study the loading and controlled release behavior of PNA-MSNs.Experimental results showed that,PNA-MSNs/DOX had good temperature and pH sensitivity,DOX drug loading efficiency was(70.4±2.9)%,and had good drug controlled release performance.Cell experiments showed that PNA-MSNs blank nano carriers had no cytotoxicity,PNA-MSNs/DOX nanocarriers were easily swallowed by human epithelial cancer cells(KB cells),showed good anticancer activity.After 10 hours of cumulative release,the cumulative drug release rates were(75±1)%(pH 7.4),(78±2)%(pH 6.5)and(82±1)%(pH 5.0),and(78±1)%,(82±2)%and(84±3)%at 25 ~oC,37 ~oC and 42 ~oC,respectively.Experiments showed that PNA-MSNs had potential application value in the field of drug controlled release.(4)Preparation and drug controlled release properties of MSNs-CTS-PNA nanocompositesBased on the synthesized MSNs and initiated by KPS,MSNs-CTS-PNA composite nanospheres with core-shell structure were prepared by polymerization of AA and NIPAM using MSNs-CTS as template.DOX as a drug model,drug loading and drug controlled release behavior of MSNs-CTS-PNA composite nanospheres were studied.Experimental results showed that,the carriers achieved the best effect on DOX loading(75.5±2.7)%.Meanwhile,MSNs-CTS-PNA/DOX showed good controlled release behavior,dual sensitivity to temperature and good pH,the same vector had no cytotoxicity.Drug-loaded carriers were also highly susceptible to phagocytosis of KB cells,showed good anticancer activity.After 10hours of cumulative release,the cumulative drug release rates were(75±2)%(pH 7.4),(79±1)%(pH 6.5)and(85±2)%(pH 5.0),and(78±1)%,(83±2)%and(87±2)%at 25 ~oC,37 ~oC and 42 ~oC,respectively.Because MSNs-CTS-PNA/DOX had good biocompatibility,biodegradability and controlled drug release behavior,double sensitivity to temperature and pH,and their good anticancer activity,MSNs-CTS-PNA composite nanocarriers were expected to have a good application prospect in the field of drug delivery and controlled release. |
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