PH And Reduction Dual Response Cross-linked Poly(ethylene Glycol)-Dextran Nanoparticles For Intracellular Drug Delivery System

In the past decades,many kinds of environment-sensitive polymeric nanoparticles(NPs)have been developed as smart nanocarriers for tumor-targeted delivery of anticancer drugs.The preclinical and clinical studies have demonstrated that the polymeric nanocarriers are able to prolong circulation time in vivo,target specific tumor tissues via the enhanced permeability and retention(EPR)effect,and reduce side effects of drug,leading to improved therapeutic efficiency.Due to the distinct tumor microenvironment as compared with normal tissues,the nanocarriers are usually designed to be stable in the blood circulation while releasing the cargos in response to biological stimuli at tumor sites or intracellular space.In these cases,various stimuli-responsiveness,such as pH,glutathione(GSH),temperature,light and enzyme,have been extensively investigated.Different functional and stimuli-responsive moieties have been incorporated into various polymers with good biocompatibility and appropriate biodegradability to develop stimuli-sensitive materials.Dextran is a family of hydrophilic polysaccharides that has been widely investigated for constructure of nanoparticulate drug delivery systems.Anticancer drug can either be conjugated directly onto the backbone of dextran or be encapsulated in the hydrophobic core of dextran-built micelles for systemic drug delivery.However,a few examples reported the preparation of core-crosslinked dextran nanoparticles for anticancer drug delivery.pH and reduction dual-sensitive nanoparticles(NPs)are the most widely used stimuli-responsive drug carriers for improving intracellular anticancer drug delivery.Pursuing high drug loading efficiency with low toxic side effect,realizing minimal drug release in normal physiological conditions while quick release under intracellular conditions still need to be solved.A kind of core cross-linked poly(ethylene glycol)-graft-Dextran nanoparticles(CPD NPs)was prepared by a simple chemical cross-linking method for reduction and pH dual response drug delivery.The resultant CPD NPs are of homogeneous spherical structure with sizes from 69 nm to 107 nm.Doxorubicin(DOX)was then loaded into the CPD NPs in high efficiency,and showing typical reduction and pH dual responsive release profiles.The flow cytometric analysis and confocal laser scanning microscopy(CLSM)confirmed that the DOX-loaded CPD NPs could be internalized into cancer cell efficiently and release DOX in intracellular environment.Furthermore,cell cytotoxicity assays indicated that the CPD NPs had good biocompatibility toward both cancerous and normal cells,while the Dox-loaded CPD NPs exhibited significant inhibition of cell proliferation in various cancercells.Therefore,this biocompatible CPD NP may have great potential for intracellular drug delivery in clinical cancer therapy.