Mesoporous Silica Nanoparticle-based Drug Delivery Research Articles

Mesoporous Silica Nanoparticle-Based Drug Delivery Systems for the Treatment of Pancreatic Cancer: A Systematic Literature Overview.

Pancreatic cancer is a devastating disease with the worst outcome of any human cancer. Despite significant improvements in cancer treatment in general, little progress has been made in pancreatic cancer (PDAC), resulting in an overall 5-year survival rate of less than 10%. This dismal prognosis can be attributed to the limited clinical efficacy of systemic chemotherapy due to its high toxicity and consequent dose reductions. Targeted delivery of chemotherapeutic drugs to PDAC cells without affecting healthy non-tumor cells will largely reduce collateral toxicity leading to reduced morbidity and an increased number of PDAC patients eligible for chemotherapy treatment. To achieve targeted delivery in PDAC, several strategies have been explored over the last years, and especially the use of mesoporous silica nanoparticles (MSNs) seem an attractive approach. MSNs show high biocompatibility, are relatively easy to surface modify, and the porous structure of MSNs enables high drug-loading capacity. In the current systematic review, we explore the suitability of MSN-based targeted therapies in the setting of PDAC. We provide an extensive overview of MSN-formulations employed in preclinical PDAC models and conclude that MSN-based tumor-targeting strategies may indeed hold therapeutic potential for PDAC, although true clinical translation has lagged behind.

A pH-responsive mesoporous silica nanoparticle-based drug delivery system for targeted breast cancer therapy.

In order to make the drug specifically aggregate at the tumor site, we had developed a targeted drug delivery system based on pH responsive mesoporous silica nanoparticles. Mesoporous silica nanoparticles (MSN-COOH) were prepared and doxorubicin (DOX) was loaded into the pores of MSN-COOH, and then polyethyleneimine (PEI) and anisamide (AA) were modified on the surface of mesoporous silica, named DOX@MSN-PEI-AA(DMPA). DMPA specifically entered tumor cells through AA-mediated receptor endocytosis; PEI dissociated from the surface of the MSN in the acidic environment of cellular lysosomes/endosomes due to protonation of PEI, resulting in steady release of the encapsulated DOX from the pores of MSN in the cytoplasm of the target cells. In vitro and in vivo anti-tumor experiments and hemolytic experiments indicated that DMPA can accurately target breast cancer cells and show excellent safety at the same time, showing great potential for tumor therapy.

Optimized mesoporous silica nanoparticle-based drug delivery system with removable manganese oxide gatekeeper for controlled delivery of doxorubicin

Rapid progress has been made for mesoporous silica nanoparticle (MSN) in recent years; however, efforts to fabricate MSN with adjustable size have been met with limited advancement in drug delivery, especially for the synthesis of MSN with adjustable size in the range of 150–300 nm. Herein we report the construction of a series of MSNs with adjustable specific surface area, size, and pore structure, depending on the different silicon monomers selected. The optimized MSN showed large specific surface area and appropriate size distribution for efficiently anchoring doxorubicin (DOX) through the imine linkage formed. Based on the remarkable features of the unique MSN, a novel MSN-based drug delivery system was prepared through the introduction of polydopamine/manganese oxide (PDA/MnO2) coating, which reduced the premature leakage of drugs in physiological environments, and yet facilitated drug release when destroyed by responding to endogenous glutathione (GSH) at the tumor sites. Notably, the transformation of MnO2 to Mn2+ resulted in the collapse of the PDA/MnO2 coating, which facilitated drug release and therefore indicated the controlled release feature. It was demonstrated that the drug-loaded MSN-based drug delivery system delivered drugs into cancer cells and showed effective inhibition against cancer cell growth. These results suggested that the emergence of MSN with adjustable size can expand the application of MSN in drug delivery.

PH/GSH-Dual-Sensitive Hollow Mesoporous Silica Nanoparticle-Based Drug Delivery System for Targeted Cancer Therapy.

The purpose of developing novel anticancer drug delivery systems (DDSs) is to efficiently carry and release drugs into cancer cells and minimize side effects. In this work, based on hollow mesoporous silica nanoparticle (HMSN) and the charge-reversal property, a pH/GSH-dual-sensitive DDS named DOX@HMSN-SS-PLL(cit) was reported. HMSN encapsulated DOX with high efficacy and was then covered by the "gatekeeper" β-cyclodextrin (β-CD) through the glutathione (GSH)-sensitive disulfide bond. Thereafter, adamantine-blocked citraconic-anhydride-functionalized poly-l-lysine (PLL(cit)-Ad) was decorated on the surface of the particles via host-guest interaction. The negatively charged carriers were stable in the neutral environment in vivo and could be effectively transported to the tumor site. The surface charge of the nanoparticles could be reversed in the weakly acidic environment, which increased the cellular uptake ability of the carriers by the cancer cells. After cellular internalization, β-CD can be removed by breakage of the disulfide bond in the presence of a high concentration of GSH, leading to DOX release. The preparation process of the carriers was monitored. The charge-reversal capability and the controlled drug-release behavior of the carriers were also investigated. In vitro and in vivo experiments demonstrated the excellent cancer therapy effect with low side effects of the carriers. It is expected that dual-sensitive DOX@HMSN-SS-PLL(cit) could play an important role in cancer therapy.

A dual-sensitive mesoporous silica nanoparticle based drug carrier for cancer synergetic therapy.

A multifunctional envelope-type mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Firstly, a kind of cell apoptosis peptide (KLAKLAK)2 (KLA) was anchored on surface of MSN via disulfide bond to obtain MSN-SS-KLA. Subsequently, anticancer drug doxorubicin hydrochloride (DOX) was loaded into the pores of MSN-SS-KLA. Then, the drug loaded MSN-SS-KLA (DOX@MSN-SS-KLA) was further coated with bovine serum albumin (BSA) to obtain a biological media stable MSN based drug delivery system (DDS), DOX@MSN-SS-KLA/BSA, for cancer synergetic therapy. The results show that stability of the DOX@MSN-SS-KLA/BSA is much better than that of DOX@MSN-SS-KLA and it could keep well dispersed in serum for more than 24 h. After accumulating at tumor site by EPR effect, the DOX@MSN-SS-KLA/BSA could be effectively phagocytosed by HeLa cells and release apoptotic peptide KLA as well as DOX simultaneously responding to reductive stimulus inside the cells. In vitro cell experiment results show that the DOX@MSN-SS-KLA/BSA complex exhibits much better inhibition on HeLa cells compared with pure DOX, indicating that co-delivery of KLA and DOX is expected to achieve synergetic therapy of cancer.

Dual-pH-sensitive mesoporous silica nanoparticle-based drug delivery system for tumor-triggered intracellular drug release

Reducing the side effects and improving the drug utilization are important work in anti-cancer drug delivery. In this paper, a novel dual-pH-sensitive drug delivery system was reported. Mesoporous silica nanoparticle (MSN) was applied to load anti-cancer drug doxorubicin hydrochloride (DOX) and was covered by mono-6-deoxy-6-EDA-β-cyclodextrine (β-CD-NH2) to block the pores through pH-sensitive boronate ester bond. And the carriers were then coated with methoxy poly(ethylene glycol) (mPEG) through another pH-sensitive benzoic imine bond. mPEG leaving studies, in vitro cellular uptake studies and the flow cytometry analysis, proved that carriers was “stealthy” at pH 7.4, but could be “activated” for cytophagy by cancer cells in weakly acidic tumor tissues (pH 6.5) due to the departure of mPEG. β-CD-NH2 leaving studies, the in vitro drug release studies and the in vitro cytotoxicity studies proved that boronate ester bond linking MSN and β-CD-NH2 was stable at both pH 7.4 and 6.5, but could be hydrolyzed intracellular to release DOX for cellular apoptosis due to the lower pH (5.0). In summary, the novel dual-pH-sensitive drug delivery system fabricated with a dynamic protection strategy should have great application potential in anti-cancer drug delivery fields.

Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors.

CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer.

Global Gene Expression Analysis of Cellular Death Mechanisms Induced by Mesoporous Silica Nanoparticle-Based Drug Delivery System

Mesoporous silica nanoparticles (MSNs), as one of the most promising inorganic drug carriers, have attracted ever increasing attention due to their unique structural, physicochemical, and biochemical features. Drug delivery systems (DDSs) based on MSNs could easily escape from endosomes after endocytosis and protect the loaded drugs from bioerosion by stable MSN carriers, efficiently deliver drugs intracellularly in a sustained release way, and consequently kill cancer cells at enhanced efficacy. However, the underlying pathways and mechanisms of cancer cell death induced by MSN-mediated drug delivery have not been well explored. In this study, we introduce gene expression analyses to evaluate the pathways and mechanisms of cancer cell death induced by a MSN-based drug delivery system. Unique changes in gene expressions and gene ontology terms, which were caused only by the MSN-based DDS (DOX-loaded MSNs, DOX@MSNs) but not by free drug doxorubicin (DOX) and/or the carrier MSNs, were discovered and proposed to be responsible for the varied cell death mechanisms, including the greatly enhanced necrosis due to amplified oxidative stress and the apoptosis related with DNA/RNA synthesis and cell cycle inhibitions. By virtue of a certain kind of synergetic biological effect between the drug and the carrier, the DOX@MSNs DDS was found capable of increasing the intracellular levels of reactive oxygen species and triggering the mitochondria-related autophagic lysosome pathway, consequently activating a specific pathway of necrosis, which is different from those by the free drug and the carrier.

A magnetic mesoporous silica nanoparticle-based drug delivery system for photosensitive cooperative treatment of cancer with a mesopore-capping agent and mesopore-loaded drug

Lately, there has been a growing interest in anticancer therapy with a combination of different drugs that work by different mechanisms of action, which decreases the possibility that resistant cancer cells will develop. Herein we report on the development of a drug delivery system for photosensitive delivery of a known anticancer drug camptothecin along with cytotoxic cadmium sulfide nanoparticles from a magnetic drug nanocarrier. Core-shell nanoparticles consisting of magnetic iron-oxide-cores and mesoporous silica shells are synthesized with a high surface area (859 m(2) g(-1)) and hexagonal packing of mesopores, which are 2.6 nm in diameter. The mesopores are loaded with anticancer drug camptothecin while entrances of the mesopores are blocked with 2-nitro-5-mercaptobenzyl alcohol functionalized CdS nanoparticles through a photocleavable carbamate linkage. Camptothecin release from this magnetic drug delivery system is successfully triggered upon irradiation with UV light, as measured by fluorescence spectroscopy. Photosensitive anticancer activity of the drug delivery system is monitored by viability studies on Chinese hamster ovarian cells. The treatment of cancer cells with drug loaded magnetic material leads to a decrease in viability of the cells due to the activity of capping CdS nanoparticles. Upon exposure to low power UV light (365 nm) the loaded camptothecin is released which induces additional decrease in viability of CHO cells. Hence, the capping CdS nanoparticles and loaded camptothecin exert a cooperative anticancer activity. Responsiveness to light irradiation and magnetic activity of the nanocarrier enable its potential application for selective targeted treatment of cancer.

Mesoporous Silica Nanoparticle-Based Double Drug Delivery System for Glucose-Responsive Controlled Release of Insulin and Cyclic AMP

A boronic acid-functionalized mesoporous silica nanoparticle-based drug delivery system (BA-MSN) for glucose-responsive controlled release of both insulin and cyclic adenosine monophosphate (cAMP) was synthesized. Fluorescein isothiocyanate-labeled, gluconic acid-modified insulin (FITC-G-Ins) proteins were immobilized on the exterior surface of BA-MSN and also served as caps to encapsulate cAMP molecules inside the mesopores of BA-MSN. The release of both G-Ins and cAMP was triggered by the introduction of saccharides. The selectivity of FITC-G-Ins release toward a series of carbohydrate triggers was determined to be fructose > glucose > other saccharides. The unique feature of this double-release system is that the decrease of FITC-G-Ins release with cycles can be balanced by the release of cAMP from mesopores of MSN, which is regulated by the gatekeeper effect of FITC-G-Ins. In vitro controlled release of cAMP was studied at two pH conditions (pH 7.4 and 8.5). Furthermore, the cytotoxicity of cAMP-loaded G-Ins-MSN with four different cell lines was investigated by cell viability and proliferation studies. The cellular uptake properties of cAMP-loaded FITC-BA-MSN with and without G-Ins capping were investigated by flow cytometry and fluorescence confocal microscopy. We envision that this glucose-responsive MSN-based double-release system could lead to a new generation of self-regulated insulin-releasing devices.

Cell-induced intracellular controlled release of membrane impermeable cysteine from a mesoporous silica nanoparticle-based drug delivery system

A mesoporous silica nanoparticle-based intracellular cysteine delivery system that could be induced and regulated by cell-produced natural antioxidants was synthesized.

Functionalized Mesoporous Silica Nanoparticle-Based Drug Delivery System to Rescue Acrolein-Mediated Cell Death

Mesoporous silica nanoparticles (MSNs) were prepared and characterized to develop a drug delivery system by loading them with hydralazine and functionalizing them with polyethylene glycol. These agents restore damaged cell membranes and ameliorate abnormal mitochondria behavior induced by the endogenous toxin acrolein. Such a formulation shows potential as a novel therapeutic agent. MSNs with encapsulated hydralazine and covalently linked with polyethylene glycol were subsequently synthesized and characterized by transmission-electron microscopy, N(2) adsorption/desorption, x-ray diffraction and UV-vis spectroscopy. MSNs exhibited large surface area, pore volume and tunable pore size. The mean particle size was 100 nm and hydralazine encapsulation efficiency was almost 25%. These were tested using PC12 in culture to restore their disrupted cell membrane and to improve mitochondria function associated with oxidative stress after exposure to acrolein. Lactate dehydrogenase, MTT, ATP and glutathione assays were used to examine the physiological functioning of the samples and the loss of lactate dehydrogenase from the cytoplasm assayed the integrity of the membranes. These evaluations are sufficient to initially demonstrate drug delivery (concentrated hydralazine) into the compromised cells cytoplasm using the MSNs as a vehicle. MSNs modified with drug/polymer constructs provide significant neuroprotection to cells damaged by a usually lethal exposure to acrolein.