Multiple Stimulative Composite Nanogels For Studies On Drug Controlled Release Behavior

Cancer is one of the most serious diseases,which causes a large number of deaths around the world each year.Although several kinds of small chemotherapeutics drugs including doxorubicin(DOX)and methotrexate(MTX)have been widely used for cancer treatment in the clinic treatment,the low therapeutic efficacy associated with multidrug resistance often requires the high amount or number of drugs injections,resulting in adverse toxicity to the organs(such as kidneys,hearts,etc.)of human or animal.One of the most popular methods to reduce the side effects of antineoplastic drugs on normal tissues is to use the drug carriers for the anticancer drug administration.Especially,the nanogels which are sensitive to tumor pathological stimuli(such as changes in pH and redox conditions)and/or exogenous stimuli(including temperature,electric/magnetic field and light)are receiving more and more attention for therapeutic delivery.In this thesis,three new multiple stimulative were prepared via in situ radical polymerization,with N-isopropylacrylamide(NIPAM)and acrylic acid(AA)as comonomers,N,N'-methylenebisacrylmide(MBA)or N,N'-bis(acryloyl)cystamine(BAC)as a crosslinker,sodium lauryl sulfate as a surfacant and potassium peroxydisulfate(KPS)as an initiator,at the presence or absence of?-cyclodextrin(?-CD).The drug loading and release behaviors of composite nanogels as well as its application in biomedical field have been studied.The main research contents and conclusions were as follows:(1)The new multiple stimulative?-CD-hybridized composite nanogels(PNACD-MBA)was synthesized with MBA as a crosslinker in the presence of?-CD.And the drug loading and release behaviors of PNACD-MBA nanogels were discussed with DOX chosen as a model drug.The results showed that PNACD-MBA nanogels displayed significant thermo/pH sensitivity,and DOX was effectively loaded to PNACD-MBA nanogels with the drug encapsulation efficiency reaching 54±5%.Moreover,PNACD-MBA/DOX nanogels presented a sustainable drug release with good temperature/pH-sensitivity.The cell studies showed that the blank PNACD-MBA nanogels have no cytotoxicity,while the DOX-loaded nanogels(PNACD-MBA/DOX)were easily to be taken by KB cells(a human epithelial carcinoma cell line)and exerted an improved anticancer cytotoxicity,which makes them be a potential for the anticancer therapeutic treatment.(2)The new composite?-CD-hybridized nanogels(PNACD-BAC)was prepared via in situ radical polymerization in the presence of?-CD using BAC as a crosslinker.The results showed that PNACD-BAC nanogels have not only obvious thermo-/pH-dual responsiveness,but also good reductive responsiveness.In order to detect how much?-CD was conjugated to the nanogels,phenolphthalein(PT)was used for the spectrophotometrical absorbances at 552 nm in PNACD-BAC nanogels before/after purification,and the data showed that~33 wt%of?-CD has been incorporated into PNACD-BAC nanogels.Similarly,DOX was chosen as a drug mode to detect the drug loading and release behaviors of PNACD-BAC nanogels,and the results exhibited that the catonic DOX was effectively loaded into PNACD-BAC nanogels(EE,71±8%),and PNACD-BAC/DOX nanogels showed excellent temperature,pH and reduction responsibility.In vitro studies,the blank nanogels did not display any cototoxicity,while PNACD-BAC/DOX nanogels presented higher antiproliferation toward KB cells.The merits of PNACD-BAC nanogels,including their degradability,cytocompatibility,drug release sustainability with thermo/pH/redox-sensitivity,and high therapeutic efficacy,make them an effect cadidate for intracellular therapeutic delivery,beyond anticancer drugs.(3)The last kind of new degradable multiple stimulative nanogels PNA-BAC were obtained with BAC as a crosslinker in the absence of?-CD.Both DOX and MTX were chosen as drug mode to detect two drugs loading and release behaviors of PNA-BAC nanogles.The results indicated that when the mass ratio of DOX and MTX reached 4:2,the drugs encapsulation effeciency of PNA-BAC was best(DOX(EE):69±3%,MTX(EE):34±6%).Interestingly,a meaningful phenomenon that the addition of MTX promoted the cumulative release of DOX from PNA-BAC/DOX/MTX nanogels,and the presence of DOX also increased the ability of MTX to be released from PNA-BAC/DOX/MTX nanogels was observed,which showed good synergistic function of both DOX and MTX in drug release process.And the cell studies showed that PNA-BAC nanogels before drug loading has no cototoxity,so the improved therapeutic efficacy to KB cells is only due to the drugs loaded nanogels PNA-BAC/DOX/MTX,where the thermosensitivity in DOX and MTX drug delivery greatly enhanced two drugs intracellular acumulation in cancer cells.The drugs loaded nanogels are of small size under physiological conditions(37 ~oC)which entice cells to endocytose them.Hence,PNA-BAC nanogels exhibited a better application prospect in drug delivey.