Zhongning Liu

Light-Induced Hydrogel Based on Tumor-Targeting Mesoporous Silica Nanoparticles as a Theranostic Platform for Sustained Cancer Treatment

Herein, we report a facile fabrication of a polymer (azobenzene and α-cyclodextrin-functionalized hyaluronic acid) and gold nanobipyramids (AuNBs) conjugated mesoporous silica nanoparticles (MSNs) to be used as an injectable drug delivery system for sustained cancer treatment. Because of the specific affinity between the hyaluronic acid (HA) on MSNs and the CD44 antigen overexpressed on tumor cells, the MSNs can selectively attach to tumor cells. The nanocomposite material then exploits thermoresponsive interactions between α-cyclodextrin and azobenzene, and the photothermal properties of gold nanobipyramids, to in situ self-assemble into a hydrogel under near-infrared (NIR) radiation. Upon gelation, the drug (doxorubicin)-loaded MSNs carriers were enclosed in the HA network of the hydrogel, whereas further degradation of the HA in the hydrogel due to the upregulation of hyaluronidase (HAase) around the tumor tissue will result in the release of MSNs from the hydrogel, which can then be taken by tumor cells and deliver their drug to the cell nuclei. This design is able to provide a microenvironment with rich anticancer drugs in, and around, the tumor tissue for time periods long enough to prevent the recrudescence of the disease. The extra efficacy that this strategy affords builds upon the capabilities of conventional therapies.

Dual responsive mesoporous silica nanoparticles for targeted co-delivery of hydrophobic and hydrophilic anticancer drugs to tumor cells

Dual responsive mesoporous silica nanoparticles (MSNs) integrating stepwise tumor targeting and co-delivery of multiple anticancer drugs were developed to attenuate the drug resistance of cancer cells (SCC cells). The nano-composite consists of MSNs as nanocarrier I for hydrophobic drugs delivery, generation 2 PAMAM dendrimer (PAMAM-G2) as nanocarrier II for hydrophilic drug delivery and hyaluronic acid (HA) as a tumor targeting agent, which effectively encapsulated drug molecules and blocked their outward diffusion from the mesopores of the MSNs before selective accumulation around the tumor. The responsive drug releases happened with cap (HA and PAMAM-G2) removal following tumor targeting and cell endocytosis, which was triggered by two intracellular stimuli, a low pH value (hydrophilic drug release) and glutathione (hydrophobic drug release). The highly selective particle-uptake by tumor cells and subsequent efficient drug co-delivery to these cells, which were directly demonstrated by fluorescence microscopy, resulted in a fourfold efficacy against tumor cells compared with normal cells, as well as higher tumor cytotoxicity than that caused by free drugs. These results indicate that this MSNs-dendrimer-HA construct, with performance of selective drug co-delivery and dual responsive drug release, could be a promising platform for cancer therapy.

Carbon-Quantum-Dots-Loaded Mesoporous Silica Nanocarriers with pH-Switchable Zwitterionic Surface and Enzyme-Responsive Pore-Cap for Targeted Imaging and Drug Delivery to Tumor.

Mesoporous silica nanocarriers with pH-switchable antifouling zwitterionic surface, enzyme responsive drug release properties and blue fluorescence are reported. Prolonged circulation in the blood system with zero premature release as well as efficient cellular uptake and intracellular drug release in tumor tissue are achieved.

Dual responsive hydrogels based on functionalized mesoporous silica nanoparticles as an injectable platform for tumor therapy and tissue regeneration

To achieve effective tumor therapy and regenerate new tissue from defects formed by tumor atrophy, a dual responsive hydrogel integrating the stepwise delivery of anti-tumor drugs/growth factors and pH/thermo induced structural transformation is developed, based on polymer (poly N-isopropylacrylamide (PNIPAM) and polyacrylic acid (PAA)) functionalized mesoporous silica nanoparticles (MSNs). Due to the thermally responsive tangle between PNIPAM chains and the pH triggered hydrogen bonds in PAA chains, these injectable MSNs would immediately switch from nanoparticles to compact hydrogels in a tumor environment (37.5 °C, pH 6.8), where the concentrated network structure in the hydrogel is in charge of the loading and local delivery of anti-tumor drugs. The MSNs serve as nanocarriers for growth factors, which are localized by crosslinked networks. The sustained release of growth factors only occurred with the cleavage of hydrogen bonds in PAA chains, which is triggered by the pH increase to 7.4 after the cure of the tumor. Moreover, the hydrogen bond cleavage would also cause the swelling of the hydrogel, which not only fills the defects but generates plenty of cell-level pores, resulting in an excellent scaffold for attachment and proliferation of healthy cells. Therefore, the dual responsive MSN-hydrogels offer a promising strategy for sequential tumor therapy and tissue regeneration.

Targeted Drug Delivery: Carbon-Quantum-Dots-Loaded Mesoporous Silica Nanocarriers with pH-Switchable Zwitterionic Surface and Enzyme-Responsive Pore-Cap for Targeted Imaging and Drug Delivery to Tumor (Adv. Healthcare Mater. 12/2016)

On page 1401 X. Chen, X. Zhang, Y. Zhou, and co-workers describe the synthesis of mesoporous silica nanocarriers with pH-switchable antifouling zwitterionic surfaces and blue fluorescence that are capable of enzyme-responsive drug release. The system combines tumor treatment and tracking. It shows great potential for cancer treatment, since it exhibits prolonged circulation in the blood system with zero premature release while offering selective cellular uptake, tumor labeling, and intracellular drug release in tumor tissue.

Stepwise co-delivery of an enzyme and prodrug based on a multi-responsive nanoplatform for accurate tumor therapy

Tumors have characteristic physiochemical conditions different from normal tissue, which makes therapy combining chemotherapeutic drugs and tumor microenvironment-responsive nanocarriers a promising route for cancer treatment. Here, we introduce a concept of integrating catalytic nanomedicine and selective chemotherapy for accurate therapy of early stage tumors by co-delivery of enzymes and prodrugs into tumor sites through a multi-responsive nanoplatform. The nanoplatform consists of a polyester-hyaluronic acid-doxorubicin (PE-HA1000k-DOX) prodrug as the corona, physiologically biodegradable silica containing disulfide bonds as the shell and hyaluronidase (absent in early stage tumors) as the core. This nanoplatform is able to quickly enter tumor cells through CD44-HA affinity. Then, the esterase and glutathione rich in tumor cells would respectively degrade the polyester and silica to release HA-DOX and hyaluronidase in a stepwise manner. Finally, highly toxic dissociative DOX is produced through decomposition of the resulting HA-DOX, catalyzed by hyaluronidase, for the apoptosis and death of the tumor cells. The properties of tumor-targeting uptake, tumor microenvironment responsiveness, efficient co-delivery of the enzyme and prodrug, and intracellular enzymatic reaction induced cytotoxicity resulted in a four-fold efficacy against tumor cells over normal cells, indicating that our nanoplatform is a promising material able to achieve both selectivity and efficiency concurrently for tumor therapeutics.

Redox-Responsive Supramolecular Micelles for Targeted Imaging and Drug Delivery to Tumor

The tumor-selective drug delivery system based on supramolecular micelles that were self-assembled by amphiphilic β-cyclodextrins (β-CD) with redox-responsiveness and fluorescence have been developed. The amphiphilic β-CD were formed by anthraquinone (AQ) and cyclodextrins with disulfide bond in between. The disulfide bond is in charge of the responsiveness, while the AQ moiety serves as fluorescent probe. The tumor targeting was introduced by the host-guest inclusion complex between β-CD and folate (FA), due to the known folate-receptor mediated endocytosis. The responsive disintegration of this β-CD-AQ-FA micelles and coinstantaneous drug releases happened with cleavage of disulfide bond following tumor targeting and cell endocytosis, which was triggered by massive glutathione in the cytoplasm of tumor cells. The highly selective particle uptake by tumor cells and subsequent efficient drug delivery to these cells, which were directly demonstrated by fluorescence microscopy, resulted in an over twofold efficacy against tumor cells compared with normal cells, as well as higher tumor cytotoxicity than that caused by free drugs. These results indicate that these β-CD-AQ-FA micelles, with performance of selective drug delivery, responsive drug release, effective drug tracking and tumor labeling, could be a promising platform for better therapeutic effects in cancer treatment.

Multiple-Responsive Mesoporous Silica Nanoparticles for Highly Accurate Drugs Delivery to Tumor Cells

A core–shell nanocarrier with triple layers, where each layer is sensitive to one specific physiological stimulus, has been fabricated for highly accurate cancer therapy. The nanocarrier consists of mesoporous silica nanoparticles (core structure for drug loading), fluorescein isothiocyanate-labeled hyaluronan (FITC–HA, first shell for imaging with enzymatic response), disulfide bond-embedded silica (SiO2, second layer with glutathione response), and switchable zwitterionic surface (third layer with pH response). The nanocarrier decorated with zwitterionic surface is able to offer long blood circulation time due to the weak nonspecific protein absorption. After these nanocarriers were gradually gathered around tumor cells through enhanced permeability and retention effect, the zwitterionic surface could switch to positive charge in low-pH environment, which was in favor of cellular uptake due to the strengthened positive nanocarrier–negative cellular membrane interaction. Once internalized into tumor cells, the high concentration of glutathione in cytoplasm could cleave disulfide bonds to remove the SiO2 shell and the HA layer would be exposed, which would be further degraded by hyaluronidase to trigger payload release. The fluorescent spectrum and images reveal that both glutathione and hyaluronidase are required for the release of preloaded drugs from these nanocarriers. By employing the multiple response, our nanocarriers could achieve effective antibiofouling ability while maintaining enhanced cellular internalization and targeted drug delivery, resulting in preferred cancer cell cytotoxicity, which is much higher than that of free doxorubicin. The in vitro data exhibited that our nanocarriers may provide an effective strategy for accurate cancer treatment.