A chitosan/mesoporous silica nanoparticle-based anticancer drug delivery system with a "tumor-triggered targeting" property.

To enhance drug utilization and reduce their side effects, the strategy of "tumor-triggered targeting" was introduced to fabricate dual-pH-sensitive chitosan (CHI)/mesoporous silica nanoparticle (MSN)-based anticancer drug delivery system (DDS) in this work. Model drug doxorubicin hydrochloride (DOX) was loaded in MSN, which was modified with benzimidazole (Bz) group. Then chitosan-graft-ß-cyclodextrin (CHI-g-CD) was applied as the "gatekeeper" to cover MSN through host-guest interaction between ß-CD and Bz. After being coated with targeting peptide adamantane-glycine-arginine-glycine-aspartic acid-serine (Ad-GRGDS), methoxy poly(ethylene glycol) benzaldehyde (mPEG-CHO) was finally grafted on CHI through the pH-sensitive benzoic imine bond. Due to the dynamic protection of PEG, the obtained carriers were "stealthy" at pH 7.4, but could reveal the shielded targeting peptide and the positive charge of CHI in the weakly acidic environment achieved a "tumor-triggered targeting". Inside cancer cells, the interaction between ß-CD and Bz group could be destroyed due to the lower pH, resulted in DOX release. Both in vitro and in vivo studies proved the DDS could targeting induce cancer cell apoptosis, inhibit tumor growth, and reduce the cytotoxicity of DOX against normal cells. It is expected that the system named DOX@MSN-CHI-RGD-PEG could be a potential choice for cancer therapy.

Preparation of thermo/redox/pH-stimulative poly(N-isopropylacrylamide-co-N,N'-dimethylaminoethyl methacrylate) nanogels and their DOX release behaviors.

Stimuli-sensitive drug delivery systems show beneficial features of both medical and pharmaceutical fields. In this article, polymeric nanogel P (N-isopropylacrylamide-N,N '-dimethylaminoethyl methacrylate [NIPAM-DMAEMA]) (PND) with pH/redox/thermo-responsivenesses was synthesized by the in situ polymerization of NIPAM and DMAEMA for the controlled release of doxorubicin hydrochloride (DOX) and N,N '-bis(acryloyl)cystamine (BAC) and N,N '-methylenebisacrylamide (MBA) act as the crosslinkers, respectively. The structure, size, and zeta potential of PND-BAC and PND-MBA were further characterized. Moreover, after loading DOX, the encapsulation efficiency and the in vitro release behavior of PND-BAC/DOX and PND-MBA/DOX nanogels were discussed in detail. Compared to PND-MBA NGs, PND-BAC nanogels have redox degradability due to the presence of the crosslinker BAC. After loading DOX, the PND-BAC/DOX nanogel showed a higher encapsulation efficiency (81.6 ± 1.2)% and thermo- and pH-responsiveness as well as redox-responsive in vitro release. These properties together with excellent environmentally sensitive properties make PND-BAC as an attractive candidate for application in drug nanocarriers for the targeted drug delivery of model payloads. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1195-1203, 2019.

Stepwise-acid-active organic/inorganic hybrid drug delivery system for cancer therapy.

Due to the difference of pH values between normal tissues, tumor tissues and intracellular environments, DOX@MSN-CD-PEG, a stepwise-acid-active organic/inorganic hybrid drug delivery system (DDS) was reported in this article. The inorganic mesoporous silica nanoparticle (MSN) was introduced for loading of doxorubicin hydrochloride (DOX). Then organic components were applied to achieve the stepwise-acid-active intracellular drug release: MSN was capped with a ß-cyclodextrine (ß-CD) based host-guest system via pH-sensitive epoxy bond. Then PEG was grafted outside of the carriers through pH-sensitive benzoic imine bond. With the protection of PEG layer, the carriers were difficult cellular uptake by normal cells but could be "acid-activated" for cytophagy by cancer cells in the slightly acidic environments in tumor tissues because of the abscission of PEG. Inside the cells, the more acidic environments could further "activate" the carriers to release DOX as the leaving of the host-guest system. The fabrication processes of DOX@MSN-CD-PEG were monitored. And the stepwise-acid-active property of which was investigated by acid-triggered PEG abscission studies and in vitro drug release studies at pH 7.4 and 6.5, respectively. The in vitro cellular cytotoxicity and cellular uptake behavior were also investigated. In summary, the stepwise-acid-active hybrid DDS should be considerable for cancer therapy.

Study on ß-cyclodextrin-complexed nanogels with improved thermal response for anticancer drug delivery.

For achievement of controllability in drug delivery, development of nanocarriers with thermal response is one of the most investigated stimulative strategies for oncological treatment. How to improve the thermosensitivity of the nanocarriers is an important factor for their successful drug delivery applications. In this study, a kind of complexed nanogels (PNACD) was developed by incorporating ß-cyclodextrin (ß-CD) into the nanogels of copolymers of N-isopropylacrylamide (NIPAM) and acrylic acid (AA) during their polymerization via in situ crosslinking of N,N'-methylenebisacrylamide (MBA) as a crosslinker. The complexed PNACD nanogels displayed a significantly enhanced thermosensitivity near body temperature compared to the ß-CD-free nanogels (PNA), which is probably associated with the rapid volumetric transformation during heating/cooling process due to the formation of complexed (decomplexed) structure between ß-CD and PNIPAM element. The PNACD nanogels can be used for loading of an anticancer drug (doxorubicin, DOX) with an encapsulation efficiency of 54±5%. The DOX-loaded nanogels displayed pH-/thermo-dual responsivenesses in drug release, which can be effectively internalized into KB cells (a human epithelial carcinoma cell line) to exert good anticancer bioactivity. This approach may enlighten design of novel nanocarriers for delivery of drugs beyond anticancer chemotherapeutic reagents.