Spatiotemporally and Sequentially-Controlled Drug Release from Polymer Gatekeeper-Hollow Silica Nanoparticles

Combination chemotherapy has become the primary strategy against cancer multidrug resistance; however, accomplishing optimal pharmacokinetic delivery of multiple drugs is still challenging. Herein, we report a sequential combination drug delivery strategy exploiting a pH-triggerable and redox switch to release cargos from hollow silica nanoparticles in a spatiotemporal manner. This versatile system further enables a large loading efficiency for both hydrophobic and hydrophilic drugs inside the nanoparticles, followed by self-crosslinking with disulfide and diisopropylamine-functionalized polymers. In acidic tumour environments, the positive charge generated by the protonation of the diisopropylamine moiety facilitated the cellular uptake of the particles. Upon internalization, the acidic endosomal pH condition and intracellular glutathione regulated the sequential release of the drugs in a time-dependent manner, providing a promising therapeutic approach to overcoming drug resistance during cancer treatment.ope

Cloaking nanoparticles with protein corona shield for targeted drug delivery

Targeted drug delivery using nanoparticles can minimize the side effects of conventional pharmaceutical agents and enhance their efficacy. However, translating nanoparticle-based agents into clinical applications still remains a challenge due to the difficulty in regulating interactions on the interfaces between nanoparticles and biological systems. Here, we present a targeting strategy for nanoparticles incorporated with a supramolecularly pre-coated recombinant fusion protein in which HER2-binding affibody combines with glutathione-S-transferase. Once thermodynamically stabilized in preferred orientations on the nanoparticles, the adsorbed fusion proteins as a corona minimize interactions with serum proteins to prevent the clearance of nanoparticles by macrophages, while ensuring systematic targeting functions in vitro and in vivo. This study provides insight into the use of the supramolecularly built protein corona shield as a targeting agent through regulating the interfaces between nanoparticles and biological systems

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer\u2019s disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53\u2019s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent\ua0anticancer agent

Enhanced precision of in-vivo stable non-covalent polymergatekeepers in mesoporous silica nanoparticles for hydrophobic drug delivery in tumor therapy

Targeted delivery mediated by ligand modified nanocarriers have been extensively pursued for cancer chemotherapy, however the efficiency is still limited by premature drug release after the administration. Herein, we represented a simple, one-pot synthesis and robust method by installing non-covalent polymer gatekeepers in mesoporous silica nanoparticles. The unmodified mesoporous silica nanocontainers have a high loading capacity for hydrophobic drugs. This is a tumor adaptable drug carrier made of disulfide bonded polyethylene glycol-pyridyl disulfide (PEG-PDS) polymer gatekeepers and can release drug upon the increased intracellular glutathione concentration. In-situ covalently crosslinked the PEG-PDS capped mesoporous silica nanoparticles have shown improved encapsulation to avoid the premature drug release. Intravenously injected non-covalent polymergatekeepers have led to hydrophobic doxorubicin in cancer cells and suppresses the tumor growth in mice. As compared to the self-assembled micelles, doxorubicin loaded polymergatekeeper mesoporous nanoparticles have shown improved tumor reducing capability

Hydrophobic drug delivery platform with polymer gatekeepers in mesoporous silica nanostructures

Among small therapeutic molecules which have been developed as an anticancer agent, many of potential active molecules are critics for obstacle and challenge in the administration due to their poor solubility in aqueous solution. Solubilizing these drugs and delivering to a target cancer site have been extensively explored with nanoscale carriers, including micelles, hollow capsules, crosslinked nanogels, cylindrical micelles, and inorganic nanoparticles. However, the versatile drug delivery platform with noncovalent gatekeepers in many kinds of hydrophobic drug molecules without premature drug release, large loading capacity and colloidal stability is still challenging. Hence we developed a simple technique by utilizing the advantage of hardcore mesoporous silica, using the biocompatible non-covalent polymergatekeepers technique. This is a versatile drug delivery platform, where different kind of hydrophobic drugs such as doxorubicin, camptothecin, paclitaxel, curcumin and tomaxifen can be loaded into the core at high capacity, without any chemical modification of the carrier. The polymer shell surface can be easily decorated with different targeting ligands with simple and mild thiol-disulfide chemistry. The drug molecules loaded in the nanocontainers can be released by the degradation of the polymer shell in controlled manner in the intracellular reducing microenvironment, which consequentially induces cell death