Sha Jin,Dian Li,Peng Yang,Jia Guo,Jennifer Q. Lu,Changchun Wang
Stimuli responsive drug delivery systems have attracted considerable attention due to their ability to deliver drugs on demand to special tissues and cells (e.g. cancer cells). In this paper, we fabricated a new kind of redox/pH dual stimuli-responsive biodegradable poly(methacrylic acid) (MAA) nanohydrogels crosslinked by N , N -bis(acryloyl)cystamine (BACy) through a facile reflux-precipitation polymerization. Subsequently polyethylene glycol (PEG) was grafted onto the surface of nanohydrogels to improve their long circulation time. This kind of PEGylated nanohydrogels could be degraded into short linear polymer chains in the solution of 10 mM glutathione (GSH) due to the sensitive disulfide bonds in the cross-linked networks. Interestingly, we found that the hydrophilic PEGylated nanohydrogels could be simultaneously loaded with hydrophilic drug doxorubicin (DOX) and hydrophobic drug paclitaxel (PTX) with high drug loading efficiency because of its regional hydrophobic nature in the nanohydrogels. The cumulative release profile showed that either lower pH (5.0) or reducing environment (GSH) or a combination could significantly accelerate the drug release from the drug-loaded nanohydrogels. In addition, the experimental results on living cells indicated that the multi-drug-loaded system had synergistic effect on cancer therapy.
Nanomedicine that combines nanomaterials and nanotechnologies has been attracting intensive attention for tumor treatment and achieved significant advances. However, their therapeutic efficiency is still limited by the passive circulating and enrichment of the currently widely used nanomaterial carries. Instead, an active nanomaterial carrier with tumor-taxis-like behavior holds the potential to further leap tumor targeting and therapeutic efficiency. Herein, for the first time, we show that a tumor microenvironment responsive disassemblable approach, based on tumor-targeted Escherichia coli bacteria linked with degradable zeolitic imidazolate framework-8 (ZIF-8) through disulfide bond-contained polymers, can deliver multiple drugs into deep tumor tissue. The carried ZIF-8 nanoparticles will detach from the Escherichia coli via disulfide bond breakage under high concentration glutathione in tumor sites. Furthermore, the small size ZIF-8 nanoparticles can penetrate whole tumor tissue and release drug molecules (doxycycline and indocyanine green) upon pH-responsive degradation. Under light irradiation, indocyanine green generates reactive oxygen species and mild hyperthermia, realizing a photodynamic/photothermal/chemical synergistic therapy along with the doxycycline. In a mouse model, the as-prepared microbial nanohybrid accumulates and releases the therapeutics throughout the tumor tissue and shows a better tumor inhibition efficacy compared to the ZIF-8 and non-disassemblable ZIF-8/microbial platforms. Thus, this work may establish a new strategy for enhancing tumor penetration and targeting and improving treatment efficiency of nanomaterials through a tumor microenvironment responsive disassemblable microbial nanohybrid.
危险品化学品经营许可证（带存储）