Study On Anticancer Drug Delivery Properties And Mechanism Of Multi-stimulative Nanocarriers Based On Poly(N-Isopropylacrylamide-Co-Acrylic Acid)

Cancer is the main reason cause of death,and chemotherapy is one of most widely used approaches for treatment of cancer diseases.Among small anticancer chemotherapeutic agent,doxorubicin(DOX)is an effective drug for cancer treatment.However,the existence of variety of drug resistance mechanisms limits its clinical applications due to the insuffcient cellular uptake,low anticancer efficiency and high side-effects.Recent research indicates that the employment of nanocarriers,especially the ones with stimulative properties can act as an effective nanoplatform for delivery of anticancer drug(s),which are able to achieve a controllable therapeutic release,preferentially with targetability to tumor sites,resulting in improved efficacy and decreased toxicity to human body.In combination with the acidic microenvironments of tumor tissue,pH sensitive nanocarriers has been developed for anticancer drug delivery,which can be further endowed with thermo-sensitivity for remote-controlled delivery of anticancer drug(s)for tempo-spatial targeting delivery upon their arrical tumor location.Although many pH/thermo-sensitive nanocarriers have been developed for antitumor drug delivery,there are still many problems to be resolved.For example,most of such carriers are not biodegradable,which may accumulate in normal cells/tissues/organs to cause a long chronic toxicity to human body.Secondly,the controllability in drug release are still needed to be improved for targeted delivery.Therefore,it is very important to develop a kind of nanosystems with multi-stimulative properties for improvement of the effective drug utilization and its efficacy.Herein,in this paper,taking advantage of thermo-sensitivity of poly(N—isopropylacrylamide)(PNIPAM),multi-stimulative P(NIPAM-AA)-based nanocarriers have been fabricated,which not only presents pH and thermo-sensitivity in drug release,but also can be degraded under reducible microenvironments of intracellular compartments as well as solid tumor.Systematic study on these nanosytems,including their morphorlogies,drug release properties and colloidal stability was investigated.The mechanisms of degradation and release were also elucidated.The main work and results were as follows.1)Study on preparation and drug release of P(NIPAM-AA)nanogels,PNA-BAC nanogels were developed by free radical precipitation polymerization of N-isopropylacrylamide(NIPAM)and acrylic acid(AA)as monomers in the presence of sodium dodecyl sulfate(SDS)as a surfactant,using N,N'—bis(acryloyl)cystamine(BAC)potassium potassium sulfate(KPS)as initiator.At the same time,PNA-MBA nanogels were synthesis by N,N'-methylene bisacrylamide(MBA)as a nondegradable crosslinker.The cationic DOX drug was loaded into the nanogels by simply mixing them in aqueous solution.The effects of BAC concentration on the particle size and Zeta potential of the nanogels were discussed.And the temperature,pH,reduction sensitivity and DOX controlled release of PNA-BAC nanogels were studied by comparing with PNA-MBA.The results show that,PNA-BAC nanogels not only presented a higher DOX drug loading capacity,but also allowed a more sustainable drug release behavior under physiological conditions.More importantly,PNA-BAC nanogels displayed thermo-induced drug release properties and an in vitro accelerated release of DOX under conditions that mimic intracellular reductive conditions and acidic tumor microenvironments.PNA-BAC-DOX nanogels can quickly be taken up by CAL-72 cells(an osteosarcoma cell line),resulting in a high DOX intracellular accumulation and an improved cytotoxicity.2)Study on preparation and drug release of P(NIPAM—AA)/MSNs nanohybrids.In order to further increase the drug loading capacity and drug release controllability,core—shell nanohybrids of mesoporous silica nanoparticles(MSNs)/P(NIPAM-AA)were developed.MSNs as core can increase drug encapsulation effieiency,while the presence of P(NIPAM-AA)nanoparticles as shell may afford more colloidal stability of nanoparticles.MSNs was prepared by using tetraethyl orthosilicate(TEOS)as silicon source and hexadecyl trimethyl ammonium bromide(CTAB)as template.Using methacrylic acid-3-(trimethoxysilyl)propyl(MPS)modified mesoporous silica with carbon carbon double bond.Infrared,N2 adsorption-desorption analyzer,and thermogravimetric analysis were used to characterize wether the modification of the material was successful.P(NIPAM-AA)/MSNs(PNA-MSNs)composite nanoparticles were developed by free radical precipitation polymerization of MPS modified-MSNs,NIPAM and AA as monomers in the presence of SDS as a surfactant,using BAC as a biodegradable crosslinker,KPS as initiator.The cationic DOX drug was loaded into the nanoparticles by simply mixing them in aqueous solution.The stability,temperature/pH/reducing sensitivity of PNA-MSNs nanoparticles were discussed.The effects of PNA-MSNs nanoparticles on DOX encapsulation efficiency and release behavior and their effects on the activity of cancer cells were studied.The results show that,compared to MSNs,PNA-MSNs nanoparticles not only presented a higher DOX drug loading capacity,but also allowed a more sustainable drug release behavior under physiological conditions.More importantly,PNA-MSNs-DOX nanoparticles nanoparticles displayed thermo-induced drug release properties and an in vitro accelerated release of DOX under conditions that mimic intracellular reductive conditions and acidic tumor microenvironments,as well as PNA-BAC-DOX nanogels.PNA-MSNs-DOX nanoparticles also can quickly be taken up by A549 cells(lung cancer cells),resulting in a high DOX intracellular accumulation and an improved cytotoxicity.