Chiral mesoporous silica nano-screws as an efficient biomimetic oral drug delivery platform through multiple topological mechanisms.

In the microscale, bacteria with helical body shapes have been reported to yield advantages in many bio-processes. In the human society, there are also wisdoms in knowing how to recognize and make use of helical shapes with multi-functionality. Herein, we designed atypical chiral mesoporous silica nano-screws (CMSWs) with ideal topological structures (e.g., small section area, relative rough surface, screw-like body with three-dimension chirality) and demonstrated that CMSWs displayed enhanced bio-adhesion, mucus-penetration and cellular uptake (contributed by the macropinocytosis and caveolae-mediated endocytosis pathways) abilities compared to the chiral mesoporous silica nanospheres (CMSSs) and chiral mesoporous silica nanorods (CMSRs), achieving extended retention duration in the gastrointestinal (GI) tract and superior adsorption in the blood circulation (up to 2.61- and 5.65-times in AUC). After doxorubicin (DOX) loading into CMSs, DOX@CMSWs exhibited controlled drug release manners with pH responsiveness in vitro. Orally administered DOX@CMSWs could efficiently overcome the intestinal epithelium barrier (IEB), and resulted in satisfactory oral bioavailability of DOX (up to 348%). CMSWs were also proved to exhibit good biocompatibility and unique biodegradability. These findings displayed superior ability of CMSWs in crossing IEB through multiple topological mechanisms and would provide useful information on the rational design of nano-drug delivery systems.

pH/H2O2 Dual-Responsive Chiral Mesoporous Silica Nanorods Coated with a Biocompatible Active Targeting Ligand for Cancer Therapy.

Nano-drug delivery systems (nano-DDSs) with an existing specific interaction to tumor cells and intelligent stimulus-triggered drug delivery performance in a tumor microenvironment (TME) remain hotspots for effective cancer therapy. Herein, multifunctional pH/H2O2 dual-responsive chiral mesoporous silica nanorods (HA-CD/DOX-PCMSRs) were creatively constructed by first grafting phenylboronic acid pinacol ester (PBAP) onto the amino-functioned nanorods, then incorporating doxorubicin (DOX) into the mesoporous structure, and finally coating with the cyclodextrin-modified hyaluronic acid conjugate (HA-CD) through a weak host-guest interaction. Under a physiological environment, the gatekeeper CD could avoid the premature leakage of DOX and minimize the side effects to normal cells. After the uptake by the tumor cells, the H2O2-sensitive moieties of PBAP were exposed and a small amount of DOX was leaked along with the shift of the supramolecular switch HA-CD under the acidic condition. Notably, the self-supplying H2O2 mediated by the released DOX in turn accelerated the PBAP disintegration, further promoted the rapid release of DOX, and increased the DOX accumulation in tumor regions. Innovatively, this nano-DDS could simultaneously achieve the tumor-targeting ability via CD44 receptor-mediated endocytosis and pH/H2O2 dual responsiveness activated by the TME and hence exhibited superior antitumor efficacy. Furthermore, HA acting as the hydrophilic shell could improve the biocompatibility of this nano-DDS.

Carboxyl-functionalized mesoporous silica nanoparticles for the controlled delivery of poorly water-soluble non-steroidal anti-inflammatory drugs.

The purpose of this study was to investigate the delivery of poorly water-soluble non-steroidal anti-inflammatory drugs (NSAIDs) by carboxyl-functionalized mesoporous silica nanoparticles (MSN-COOH) with high specific surface area (SBET). In this study, MSN-COOH was prepared by collaborative self-assembly using cetyltrimethylammonium bromide (CTAB) as template and hydrolysis (3-triethoxyl-propyl) succinic anhydride (TESPSA) as co-structure auxiliary directing agent (CSDA). The drug delivery systems were constructed with NSAIDs including Nimesulide (NMS) and Indomethacin (IMC) as model drugs. Moreover, the characterization techniques, hemolysis and bio-adsorption testes, in vitro drug release and in vivo biological studies of MSN-COOH were also carried out. The characterization results showed that MSN-COOH is spheres with clearly visible irregular honeycomb nanopores and rough surface (SBET: 1257 m2/g, pore volume (VP): 1.17 cm3/g). After loading NMS/IMC into MSN-COOH with high drug loading efficiency (NMS: 98.7 and IMC: 98.2%), most crystalline NMS and IMC converted to amorphous phase confirmed using differential scanning calorimeter (DSC) and X-ray power diffraction (XRD) analysis. Meanwhile, MSN-COOH significantly increased the dissolution of NMS and IMC compared with non-functionalized mesoporous silica nanoparticles (MSN), which was also confirmed by wettability experiments. The results of in vivo biological effects showed that MSN-COOH had higher bioavailability of NMS and IMC than MSN, and exerted strong anti-inflammatory effects by delivering more NMS and IMC in vivo. STATEMENT OF SIGNIFICANCE: This study successfully prepared MSNs-COOH (mesoporous silica nanoparticles modified with negatively charged carboxyl groups on the surface and in the pores) with high specific surface area and pore volume by using the negatively charged carboxyl group (hyd-TESPSA) and the positively charged CTAB self-assembled through electrostatic attraction under alkaline conditions. The drug delivery systems were constructed with Nimesulide (NMS) and Indomethacin (IMC) as model drugs. The results showed MSNs-COOH had high drug loading capacity and also exhibited good in vitro drug release properties. Interestingly, NMS loaded MSNs-COOH also had a potential pH responsive release effect. In vivo biological studies revealed that NMS/IMC loaded MSNs-COOH could evidently improve the bioavailability and played the strong anti-inflammatory effects.

Facile synthesis of PEI-based crystalline templated mesoporous silica with molecular chirality for improved oral delivery of the poorly water-soluble drug.

The aim of this study was to build up a novel chiral mesoporous silica called PEIs@TA-CMS through a facile biomimetic strategy and to explore its potential to serve as a drug carrier for improving the delivery efficiency of poorly water-soluble drug. PEIs@TA-CMS was synthesized by using a chiral crystalline complex associated of tartaric acid and polyethyleneimine (PEIs) as templates, scaffolds and catalysts. The structural features including morphology, size, pore structure and texture properties were systematacially studied. The results showed that PEIs@TA-CMS was monodispersed spherical nanoparticles in a uniformed diameter of 120-130 nm with well-developed pore structure (SBET: 1009.94 m2/g, pore size <2.21 nm). Then PEIs@TA-CMS was employed as nimodipine (NMP) carrier and compared with the drug carry ability of MCM41. After drug loading, NMP was effectively transformed from the crystalline state to an amorphous state due to the space confinement in mesopores. As expected, PEIs@TA-CMS had superiority in both drug loading and drug release compared to MCM41. It could incorporate NMP with high efficiency, and the dissolution-promoting effect of PEIs@TA-CMS was more obvious because of the unique interconnected curved pore channels. Meanwhile, PEIs@TA-CMS could significantly improve the oral adsorption of NMP to a satisfactory level, which showed approximately 3.26-fold higher in bioavailability, and could effectively prolong the survival time of mice on cerebral anoxia from 10.98 to 17.33 min.

Advances in regulating physicochemical properties of mesoporous silica nanocarriers to overcome biological barriers.

Mesoporous silica nanoparticles (MSNs) with remarkable structural features have been proven to be an excellent platform for the delivery of therapeutic molecules. Biological barriers in various forms (e.g., mucosal barrier, cellular barrier, gastrointestinal barrier, blood-brain barrier, and blood-tumor barrier) present substantial obstacles for MSNs. The physicochemical parameters of MSNs are known to be effective and tunable not only for load and release of therapeutic molecules but also for their biological responsiveness that is beneficial for cells and tissues. This review innovatively provides a description of how and why physicochemical properties (e.g., particle size, morphology, surface charge, hydrophilic-hydrophobic property, and surface modification) of MSNs influence their ability to cross the biological barriers prior to reaching targeted sites. First, the structural and physiological features of biological barriers are outlined. Next, the recent progresses in the critical physicochemical parameters of MSNs are highlighted from physicochemical and biological aspects. Surface modification, as an important strategy for achieving rapid transport, is also reviewed with special attention to the latest findings of bioactive groups and molecular mechanisms. Furthermore, advanced designs of multifunction intelligent MSNs to surmount the blood-tumor barrier and to actively target tumor sites are demonstrated in detail. Lastly, the biodegradability and toxicity of MSNs are evaluated. With perspectives for their potential application and biosafety, the clues in summary might lead to drug delivery with high efficiency and provide useful knowledge for rational design of nanomaterials.

Dual response to pH and chiral microenvironments for the release of a flurbiprofen-loaded chiral self-assembled mesoporous silica drug delivery system.

This study examined the effects of pH and chirality on the release of flurbiprofen (FP)-loaded chiral (L/D) self-assembled mesoporous silica nanoparticles (CSA-L/D-MSNs), which were synthesized using cationic cetyltrimethyl ammonium bromide (CTAB) as a template and chiral modified using L/D-tartaric acids. The morphology and physicochemical properties of the CSA-L/D-MSNs were systemically determined and compared with those of non-functionalized mesoporous silica nanoparticles (MSN). The results showed that the CSA-L/D-MSNs were spherical nanoparticles, and the chirality in the L/D-tartaric acids was successfully imparted to the CSA-L/D-MSNs. FP could be loaded into the CSA-L/D-MSNs and was effectively transformed from the crystalline state to an amorphous state after drug loading due to the finite size effect. The release of FP@CSA-L/D-MSNs was faster than that of FP in a pH 1.2 medium and slower in a pH 6.8 medium, and it was better than that of FP@MSNs in both release mediums. Meanwhile, the FP@CSA-L/D-MSNs exhibited a clearly enhanced pH response because the negatively charged carboxyl groups on their surface induced stronger electrostatic repulsion between FP and CSA-L/D-MSNs. Moreover, the effect of the chiral environment on the release of FP@CSA-L/D-MSNs was further studied by introducing small-molecule chiral additives (L/D-alanine). It was found that the release of FP was inhibited in a chiral environment. Particularly, the CSA-L/D-MSNs began to exert the chiral recognition function, in which the CSA-L-MSN responded to chiral stimuli and enhanced the cumulative release amount from 84.25 %-89.11 % in a pH 6.8-L medium, while the CSA-D-MSN showed a suppressed release in the pH 6.8-L medium. Notably, the CSA-L/D-MSNs exhibited intelligent drug release by both chirality response and pH response, and will provide valuable guidance for the design of drug delivery systems.

Biomimetic Synthesis and Evaluation of Interconnected Bimodal Mesostructured MSF@Poly(Ethyleneimine)s for Improved Drug Loading and Oral Adsorption of the Poorly Water-Soluble Drug, Ibuprofen.

PURPOSE: The aim of this study was to improve the oral bioavailability and anti-inflammatory activity of the poorly soluble drug ibuprofen (IBU) by employing a new kind of poly(ethyleneimine)s (PEIs)-based mesocellular siliceous foam (MSF) called B-BMSF@PEI as drug carrier. METHODS: B-BMSF@PEI was biomimetically synthesized by using PEIs as templates, catalysts and scaffolds under ambient conditions, and the structural characteristics, including size, morphology, mesoscopic structure and pore properties, were estimated by TEM, SEM, FTIR and N2 desorption/adsorption measurement. Then, IBU was incorporated into B-BMSF@PEI at the drug:carrier weight ratio of 1:1. The structural features of IBU before and after drug loading were systemically characterized. IBU and B-BMSF@PEI were then subject to in vitro drug release study and wettability analysis. Finally, in vivo pharmacokinetics and anti-inflammatory pharmacodynamics studies were carried out to evaluate the efficacy of B-BMSF@PEI on improving the oral adsorption of IBU. RESULTS: The results demonstrated that B-BMSF@PEI was a meso-meso porous silica material with foam appearance. It consisted of uniform spherical cells (40 nm) with interconnected pore networks. IBU can be successfully loaded into B-BMSF@PEI with high efficiency (as high as 39.53%), and crystal IBU was effectively converted to an amorphous state during this process. Benefiting from the great architectures of B-BMSF@PEI, IBU/B-BMSF@PEI performed good wetting property and significantly improved the dissolution rate in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Notably, IBU exhibited very satisfactory relative bioavailability (681.4%) and anti-inflammatory effects (the inhibition rates were between the ranges of 113.5% to 1504.3%). CONCLUSION: B-BMSF@PEI with bimodal mesoporous system and interconnected nanopores was obtained owing to the dynamic self-assembly functions of PEIs. It had superiority in drug loading and could improve the oral adsorption of ibuprofen to a satisfactory level.