Fabrication And Antitumor Activity Of Multi-Stimuli Responsive Nanogels

Due to high morbidity and mortality of cancer,its treatment has become a research focus in the world today.Chemotherapy is an indispensable choice for cancer therapy.However,conventional chemotherapy suffers from several disadvantages,such as poor bioavailability and side effects due to nonspecific drug distribution,and drug resistance.In order to precisely control the action site of anticancer drugs,stimulation-responsive nanogels systems have been proposed by the researchers.They possess the following advantages in the field of tumor therapy:(1)They could encapsulate and deliver multiple drugs;(2)They can achieve accumulation at the target site by enhanced permeability and retention effect or targeting functional groups,and then release antitumor drugs at this site;(3)Based on their structural and conformational specificity,nanocarriers could respond to various internal stimuli or external triggers(redox sensitivity,pH sensitivity,enzyme sensitivity,light sensitivity,ultrasound sensitivity,etc.)to precisely control drug release.Here,natural polymers(sodium alginate(SA),hyaluronic acid(HA))with excellent biocompatibility,biodegradability and easy functionalization were designed as multi-stimuli responsive hybrid nanogels by combining with polydopamine(PDA).The hybrid nanogels were a kind of intelligent drug delivery system for drug targeted delivery and intelligent controlled release,which had good antitumor activity in vitro.1)Preparation and antitumor activity of redox/pH dual responsive sodium alginate/polydopamine nanogelsA dual-stimuli responsive hybrid nanogels system consisting of sodium alginate and polydopamine was developed for the controlled drug release with abnormal microenvironment in tumor sites.First,PDA NPs with a size of 136±3 nm were obtained by solution oxidation in Tris buffer(10 m M,pH 10.5).Then hybrid nanogels(PDGS)were fabricated by incorporating carboxyl-modified PDA NPs into SA via a double emulsion-solvent evaporation method.The obtained PDGS nanogels were cross-linked through cystamine containing sulfur-sulfur bond.Their degradation behavior and the corresponding morphological variation were explored by DLS,TEM,etc.Antitumor drug doxorubicin(DOX)was loaded in PDGS nanogels by non-covalent interaction,and the stimuli-responsive drug release was analyzed.The results showed that PDGS nanogels had an enhanced cumulative DOX release after 48 h under both acidic(61.1±1.8%)and reducible(61.7±1.2%)conditions which were about double time of that of the samples performed under normal conditions(35.5±0.9%).In addition,PDGS/DOX showed great anticancer effect in vitro,which makes them be a potential for the field of tumor therapy.2)Study on preparation and targeted drug delivery of multi-stimuli responsive nanogels based on hyaluronic acidTargeted drug delivery systems could maximize the drug bioavailability and meanwhile minimize side effects to normal cells.Hence,this study developed a targeted drug delivery system based on the affinity between HA and cluster determinant 44(CD44)receptors overexpressed in tumor cells.We used PDANPs as a cross-linking agent to cross-link cystamine modified hyaluronic acid to form this system.TEM results showed that PDH nanogels had core-shell structure and enzymatic degradation.Due to the presence of disulfide bonds and HA,PDH/DOX could respond to multiple stimuli pH,redox and HAase to trigger the drug releas,and cotriggered release with cumulative release up to 80±0.9% at 48 h was found to be faster than single triggered release.Moreover,PDH/DOX had enhanced cellular uptake and high intracellular drug accumulation in A549 cells(CD44 overexpression),showing a substantial antitumor effect.