Search

Mucosal immunization is a powerful weapon against viral infection. In this paper, large pore mesoporous silica nanoparticles (LMSN) with different particle sizes were synthesized for loading influenza split vaccine (SV) to explore the effect of nanoparticle sizes on mucosal immunization and adjuvant efficacy. Interestingly, it was found that among the three particle sizes of nanoparticles, only LMSN-M with around 250 nm could significantly enhance the mucosal immune effect of SV, possessing adjuvant effect. The results indicated that particle size affected the adjuvant effect of LMSN. There was no apparent difference in vaccine loading capacity of LMSN with different particle sizes, but the release of SV depended on the pore length of LMSN. The adjuvant effect of LMSN-M was attributed to its higher cellular uptake performance, intestine absorption and transport efficiency, and the ability to stimulate the maturation of dendritic cells. Simultaneously, compared with LMSN-S and LMSN-L, the more retention of LMSN-M in mesenteric lymph nodes increased the chance of interaction between vaccine and immune system, resulting in the enhanced immunity. This is the first time to study the impact of particle size of LMSN adjuvant on improving mucosal immunity of oral influenza vaccine, and the present work provides a scientific reference for adjuvant design of oral vaccine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) is limited in tumor therapy due to the mature antioxidant barrier of tumor microenvironment (TME) and phototoxicity/easy-degradation characteristics of photosensitizers. Therefore, we prepared Cu 2+ -doped hollow carbon nanoparticles (CHC) to protect the loaded photosensitizers and sensitize TME by glutathione-depletion and peroxidase (POD)-like activity for enhanced PDT. CHC significantly increased the maximum speed of POD-like reaction (V m ) of 8.4 times. By coating with hyaluronic acid (HA), the active sites on CHC were temporarily masked with low catalytic property, and restored in response to the overexpressed hyaluronidase in TME. Meanwhile, due to the excellent photothermal conversion efficiency (32.5 %) and hollow structure of CHC, the loaded photosensitizers were well protected from sunlight activation-induced unwanted phototoxicity and rapid degradation under the near-infrared light irradiation. In-vivo anti-tumor experiments demonstrated that the combination of photothermal-photodynamic effect achieved the best anti-tumor effect (tumor inhibition rate at 87.8 %) compared with any monotherapy. In addition, the combination of photothermal and photodynamic effect could efficiently suppress the cell migration, manifesting the reduced number of lung metastasized nodules by 74 %. This work provides an integrated platform for photosensitizers protection and TME sensitization for enhanced PDT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered an elegant solution to eradicate tumors due to its minimal invasiveness and low systemic toxicity. Nevertheless, it is still challenging for phototherapy to achieve ideal outcomes and clinical translation due to its inherent drawbacks. Owing to the unique biological functions, diverse gases have attracted growing attention in combining with phototherapy to achieve super-additive therapeutic effects. Specifically, gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S) have been proven to kill tumor cells by inducing mitochondrial damage in synergy with phototherapy. Additionally, several gases not only enhance the thermal damage in PTT and the reactive oxygen species (ROS) production in PDT but also improve the tumor accumulation of photoactive agents. The inflammatory responses triggered by hyperthermia in PTT are also suppressed by the combination of gases. Herein, we comprehensively review the latest studies on gas-synergized phototherapy for cancer therapy, including (1) synergistic mechanisms of combining gases with phototherapy; (2) design of nanoplatforms for gas-synergized phototherapy; (3) multimodal therapy based on gas-synergized phototherapy; (4) imaging-guided gas-synergized phototherapy. Finally, the current challenges and future opportunities of gas-synergized phototherapy for tumor treatment are discussed. STATEMENT OF SIGNIFICANCE: 1. The novelty and significance of the work with respect to the existing literature. (1) Strategies to design nanoplatforms for gas-synergized anti-tumor phototherapy have been summarized for the first time. Meanwhile, the integration of various imaging technologies and therapy modalities which endow these nanoplatforms with advanced theranostic capabilities has been summarized. (2) The mechanisms by which gases synergize with phototherapy to eradicate tumors are innovatively and comprehensively summarized. 2. The scientific impact and interest. This review elaborates current trends in gas-synergized anti-tumor phototherapy, with special emphases on synergistic anti-tumor mechanisms and rational design of therapeutic nanoplatforms to achieve this synergistic therapy. It aims to provide valuable guidance for researchers in this field., Competing Interests: Declaration of Competing Interest The authors declare there is no conflict of interests., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Glycolysis plays a vital role in the development and progression of tumors. Inhibiting glycolysis via smart and safe methods serves as a promising target for cancer therapy. Here, an oral "sugar-coated bullet" aiming at intervening Warburg effect is designed by coating colloidal mesoporous silica nanoparticles (CMS) encapsulating glycolysis inhibitor shikonin (SHK) with dextran, namely DCMS/SHK. The solubility and drug-loading capacity of SHK were enhanced by the special structure of CMS. Besides, the tempting bullets possess the spatial-to-point cascade targeting ability in delivering SHK from the colonic lumen to colon cancer cells and finally to PKM2. After DCMS/SHK reaches the colon, the dextran is hydrolyzed by dextranase especially existing in the colon site to glucose and the carriers become glucose-coated nanoparticles. The glucose-cloak nanoparticles would be largely endocytosed by tumor cells and complete the efficient delivery of SHK. The encapsulated SHK can prevent the glycolysis of cancer cells and thus inhibit tumor growth effectively. This work presents an ingenious cascade colon-targeting strategy to treat colon cancer by destroying cell energy metabolism., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Yuling Mao reports financial support was provided by National Natural Science Foundation of China. Yuling Mao reports financial support was provided by Doctoral Start-up Foundation of Liaoning Province., (Copyright © 2022. Published by Elsevier B.V.)

Photodynamic therapy (PDT) has been thriving in the theranostics of cancer in recent years. However, due to a series of problems such as high concentration of GSH and insufficient O 2 partial pressure in the tumor micro-environment, it is difficult to achieve the desired therapeutic effects with single PDT. Mesoporous carbon (MC-COOH) has been widely used in photothermal therapy (PTT) due to its high photothermal conversion efficiency and drug loading. In addition, we have discovered that MC-COOH owned high-efficiency glutathione oxidase-like activity for intracellular lasting GSH consumption. Hence, a smart mesoporous carbon nanozyme (CCM) was designed as a dual-GSH depletion agent and O 2 generator combined with PTT to overcome the dilemma of PDT. MnO 2 -doped carbon nanozyme (MC-Mn) was developed as the photothermal vehicles for the efficient loading of photosensitizer (Ce6). Subsequently, 4T1 membrane-coated nanozyme (Ce6/CCM) was constructed to achieve homologous targeting capability. The carbon nanozyme owned the sustained dual-GSH depletion function through MC-COOH and MnO 2 , which greatly destroyed the antioxidant system of the tumor. Meanwhile, MnO 2 could produce affluent O 2 in the presence of H 2 O 2 , thereby alleviating the hypoxic state of tumor tissues and further promoting the generation of ROS. In addition, the novel carbon nanozyme was designed as photoacoustic imaging (PAI) agent and magnetic resonance imaging (MRI) contrast for real-time imaging during tumor therapy. In summary, this work showed that the biomimetic carbon nanozyme could be used as dual-GSH depletion agent and O 2 generator for dual-mode imaging-guided PTT-PDT. STATEMENT OF SIGNIFICANCE: - MC-COOH with highly efficient GSH-OXD activity was first discovered and applied in PDT. - MnO 2 acted as an O 2 generator and GSH depletion agent to enhance PDT. - The tumor-targeting ability of the nanozyme was improved by cell membrane camouflage. - CCM nanozyme possesses both PAI and MRI dual-mode imaging modalities to guide PDT/PTT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

The accumulation of nanomedicines in tumor tissues determines their therapeutic efficacy. We herein exploit the tropism of macrophages to improve the accumulation and retention time of nanomedicine at tumors. Interestingly, macrophages are not merely as transporters, but killers activated by nanomedicine. The system(M@C-HA/ICG) was established by decorating macrophages with hyaluronic acid-modified hollow mesoporous carbon (C) nanoparticles loading indocyanine green (ICG). Notably, C nanoparticles with superior photothermal conversion capability not merely guarantee the efficient delivery of ICG through high drug loading efficiency and inhibiting the premature leaky, but effectually activate the polarization of macrophages. The results exhibited that those activated macrophages could release pro-inflammatory cytokines (NO, TNF-α, IL-12), while M@C-HA/ICG afforded about 2-fold higher tumor accumulation compared with pure nanoparticle C-HA/ICG and produced heat and singlet oxygen ( 1 O 2 ) under irradiation of an 808 nm laser, realizing the combination of photodynamic therapy (PDT), photothermal therapy (PTT) and cytokines-mediated immunotherapy. Specially, we also investigated the relationship of singlet oxygen ( 1 O 2 ) or temperature and tumor-killing activity for understanding the specific effectual procedure of PDT/PTT synergistic therapy. Overall, we firstly established an "all active" delivery system integrating the features of nanomedicine with biological functions of macrophages, providing a novel insight for cell-mediated delivery platform and tumor targeted multimodality anti-cancer therapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Efficient delivery of payload to intracellular targets has been identified as the central principle for nanomedicine development, while the extracellular targets are equally important for cancer treatment. Notably, the contribution of extracellularly distributed nanoparticles to therapeutic outcome is far from being understood. Herein, we develop a pH/light dual-responsive monochromatic ratiometric imaging nanoparticle (MRIN), which functions through sequentially lighting up the intracellular and extracellular fluorescence signals by acidic endocytic pH and near-infrared light. Enabled by MRIN nanotechnology, we accurately quantify the extracellular and intracellular distribution of nanoparticles in several tumor models, which account for 65-80% and 20-35% of total tumor exposure, respectively. Given that the majority of nanoparticles are trapped in extracellular regions, we successfully dissect the contribution of extracellularly distributed nanophotosensitizer to therapeutic efficacy, thereby maximize the treatment outcome. Our study provides key strategies to precisely quantify nanocarrier microdistribtion and engineer multifunctional nanomedicines for efficient theranostics., (© 2022. The Author(s).)

Photoactivated therapeutic strategies (photothermal therapy and photodynamic therapy), due to the adjusted therapeutic area, time and light dosage, have prevailed for the fight against tumors. Currently, the monotherapy with limited treatment effect and undesired side effects is gradually replaced by multimodal and multifunctional nanosystems. Mesoporous silica nanoparticles (MSNs) with unique physicochemical advantages, such as huge specific surface area, controllable pore size and morphology, functionalized modification, satisfying biocompatibility and biodegradability, are considered as promising candidates for multimodal photoactivated cancer therapy. Excitingly, the innovative nanoplatforms based on the mesoporous silica nanoparticles provide more and more effective treatment strategies and display excellent antitumor potential. Given the rapid development of antitumor strategies based on MSNs, this review summarizes the current progress in MSNs-based photoactivated cancer therapy, mainly consists of (1) photothermal therapy-related theranostics; (2) photodynamic therapy-related theranostics; (3) multimodal synergistic therapy, such as chemo-photothermal-photodynamic therapy, phototherapy-immunotherapy and phototherapy-radio therapy. Based on the limited penetration of irradiation light in photoactivated therapy, the challenges faced by deep-seated tumor therapy are fully discussed, and future clinical translation of MSNs-based photoactivated cancer therapy are highlighted., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Excellent efficiency of combinational therapy of chemotherapy and photodynamic therapy (PDT) highly depends on the amounts of drug and oxygen in tumor tissue. However, how to cleverly promote drug release accompanied with improving oxygen concentration remains a challenge. Herein, we proposed a gas-generator that realized a high drug loading and integrated facilitation of drug release with oxygen replenishment into a single and simple system, utilizing huge cavities and mesoporous channels of hollow mesoporous silica nanoparticles (HMSNs) for encapsulating oxygen (O 2 ) saturated perfluoropentane (PFP) droplets, indocyanine green (ICG) and doxorubicin (DOX), biocompatible polydopamine (PDA) as the gatekeepers. Under irradiation of 808 nm laser, the thermal effect of PDA caused PFP droplets occur liquid-gas phase transition that triggered the burst release of DOX and O 2 , finally amplifying the synergetic effects of PDT and chemotherapy both in vitro and in vivo. The influence of PFP, GSH and laser on drug release kinetic was explored through mathematical models. Notably, the mechanism of gas-generator on accelerating drug release under irradiation based on doing volume work and enhancing diffusion coefficient was clarified by researching the relation between DOX release, PFP release and temperature change. Additionally, the way of replenishing O 2 did not rely on intracellular components but timely offered abundant "fuels" for producing reactive oxygen species (ROS) when compared with traditional manners. This work provides a new research strategy for boosting drug release and opens an avenue for constructing multifunctional controlled delivery systems., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Triple-negative breast cancer (TNBC) have been considered as the most malignant subtype of breast cancer with leading incidence and mortality among females. Herein, photo-responsive prodrug nanoparticles (AlP/CPT-NPs) were designed with efficient cytoplasmic delivery of anti-cancer agent for cooperative photodynamic-chemotherapy. AlP/CPT-NPs were prepared using photosensitizer Al(III) phthalocyanine chloride disulfonic acid (AlP) and ROS-activatable camptothecin prodrug (CPT-PD). AlP/CPT-NPs could induce intracellular 1 O 2 generation upon light exposure, which not only initiate immediate disassembly of AlP/CPT-NPs but also promote cytoplasmic delivery of CPT through 1 O 2 -mediated lysosomal rupture. The released intracellular CPT could be translocated into nuclei in only 5 min post-irradiation. Consequently, AlP/CPT-NPs efficiently suppressed the tumor growth and metastasis of TNBC in a spatiotemporally controlled manner, providing a promising option for effective treatment of metastatic TNBC. STATEMENT OF SIGNIFICANCE: Breast cancer is a complex disease with leading incidence among females, in which triple-negative breast cancer (TNBC) is considered as the most malignant subtype with increased risk of resistance, recurrence and metastasis. Herein, we designed photo-responsive prodrug nanoparticles (AlP/CPT-NPs) for synergistic treatment of metastatic TNBC. Upon 660 nm light exposure, the 1 O 2 generated by AlP/CPT-NPs could initiate immediate disassembly of AlP/CPT-NPs and further promote cytoplasmic delivery of the therapeutic payloads (camptothecin, CPT). The prepared AlP/CPT-NPs induced potent in vivo phototherapeutic damage through photodynamic-chemotherapy, resulting in complete tumor ablation with metastasis suppression., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest, (Copyright © 2021. Published by Elsevier Ltd.)

The low power photothermal therapy can reduce the tissue damage caused by laser irradiation, thus the near-infrared (NIR) absorbing vehicles with high photothermal conversion efficiency are demanded in the low power treatment. Herein, the NIR-absorbing agent polydopamine (PDA) and carbon dots (CDs) were gated on the openings of hollow mesoporous carbon (HMC) to construct a photothermal enhanced multi-functional system (HMC-SS-PDA@CDs). Interestingly, the fluorescence emission wavelength of HMC-SS-PDA@CDs was red-shifted by FRET effect between PDA and CDs, which solved the dilemma of fluorescence quenching of carbon-based materials and was more conducive to cell imaging. The modification of PDA@CDs not only acts as the gatekeepers to realize multi-responsive release of pH, GSH and NIR, but also endows the HMC vehicle with excellent photothermal generation capacity, the possibility for bio-imaging as well as the enhanced stability. Naturally, both the cytological level and the multicellular tumor sphere level demonstrate that the delivery system has good low-power synergistic therapeutic with combination index (CI) of 0.348 and imaging effects. Meanwhile, the combined treatment group showed the highest tumor inhibition rate of 92.6% at 0.75 W/cm 2 . Therefore, DOX/HMC-SS-PDA@CDs nano-platform had broad application prospects in low power therapy and convenient imaging of carbon-based materials., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Oral delivery of protein or peptide drugs confronts several barriers, the intestinal epithelium and the mucus barrier on the gastrointestinal tract is deemed to be the toughest obstacles. However, overcoming these two obstacles requires contradictory surface properties of a nanocarrier. In the present work, mesoporous silica nanoparticles (MSNs) were modified with deoxycholic acid (DC) and coated with sulfobetaine 12 (SB12) for the first time to achieve both improved mucus permeation and transepithelial absorption. MSNs modified with stearic acid and coated with dilauroylphosphatidylcholine (DLPC) or Pluronic P123 were also prepared as controls. The SB12 coated DC modified MSN had high drug loading of 22.2%. The zwitterion coating endows the MSN improved mucus penetrating ability. In addition, the carrier also showed remarkable affinity with epithelial cells. The cellular uptake was significantly improved (10-fold for Caco-2 cells and 8-fold for E12 cells). The results also indicated that the DC modified carrier was able to avoid entry into lysosomes. It can increase the absorption of loaded insulin in all intestine segments and showed outstanding hypoglycemic effect in diabetic rats. The results suggest the zwitterion-functionalized MSNs might be a good candidate for oral protein delivery., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this work, a traceable dual-porous mesoporous silica-coated mesoporous carbon nanocomposite (MCN@Si) with high drug loading capacity and high photothermal conversion efficiency (30.5 %) was successfully prepared. Based on the nanocomposite, a pH/redox/near infrared (NIR) multi-stimuli responsive drug delivery system was constructed to realize the accurate drug delivery, drug controlled release and chemo-photothermal synergistic antitumor therapy. MCN@Si was used as a vehicle to load doxorubicin (DOX) with a high drug loading efficacy of 48.2 % and a NIR absorbance agent for photothermal therapy and NIR thermal imaging. Carbon dots (CDs) with proper size were covalently attached to the surface of MCN@Si via disulfide bonds to block the mesopores, preventing DOX premature release from DOX/MCN@Si-CDs. Besides, CDs were served as fluorescent probe to prove the visualization potential of the drug delivery system. DOX was rapidly released at the condition of low pH and high GSH concentration due to the breakage of disulfide bonds and protonation of DOX. Moreover, the local hyperthermia generated by MCN@Si-CDs under NIR irradiation could not only directly kill cells, but also accelerate DOX release and enhance cells sensitivity and permeability. Two-dimensional cells and three-dimensional tumor spheroids assays illustrated that DOX/MCN@Si-CDs + NIR group exhibited a superior thermochemotherapy synergistic treatment effect and the combination index (CI) was 0.378. Biodistribution study showed the biosecurity of preparations and its prolonged detention time in tumor sites. Besides, antitumor experiment in vivo also performed the excellent synergistic inhibition effect. All the results demonstrated that DOX/MCN@Si-CDs is a traceable multi-stimuli responsive nanodelivery system and can achieve efficient chemo-photothermal synergistic antitumor therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Numerous types of mesoporous silica nanoparticles (MSNs) have been studied as carriers for small molecular drugs. However, few reports have been conducted on small MSNs having large pores, and that are suitable for loading and orally delivering therapeutic proteins. In particular, their protective properties against aggregation and enzymatic hydrolysis of loaded proteins have been rarely studied. In this study, mesocellular silica foams (MCFs) with large and different pore sizes were prepared. The loading and release behaviors of three model proteins with different molecular weights were studied. The protective properties of the MCFs against enzymatic hydrolysis of the loaded proteins were tested by sodium dodecyl sulfate polyacrylamide gel electrophoresis and high-performance liquid chromatography. The protecting effects of the MCFs against conformational change and aggregation of the loaded proteins were evaluated by circular dichroism and synchronous fluorescence spectra. Diabetic mice were inducted to evaluate in a preliminary manner the in vivo hypoglycemic effect of insulin loaded MCFs. The prepared MCFs showed rapid and high drug loading (up to 43%) of proteins. The release of proteins was tunable depending on the pore size. The lysozyme loaded MCFs could release 87% intact protein after incubation with pancreatin for 0.5 h. The digestion times for the insulin loaded in MCFs were prolonged to twice that of naked insulin. The secondary conformational changes for the insulin loaded in MCFs were only 1/40 to 1/20 of that of naked insulin incubated with Zn 2+ . Orally administered insulin-loaded MCF could reduce the blood glucose level to 69%. The prepared MCFs could effectively protect the loaded proteins from aggregation and enzymatic hydrolysis, thus exhibiting potential for application as carriers for protein delivery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aiming at the inefficiency and toxicity in traditional antitumor therapy, a novel multifunctional nanoplatform was constructed based on hollow mesoporous carbon (HMC) to achieve triple stimuli response and dual model antitumor therapy via chemo-photothermal synergistic effect. HMC was used as an ideal nanovehicle with a high drug loading efficiency as well as a near-infrared (NIR) photothermal conversion agent for photothermal therapy. Acid-dissoluble, luminescent ZnO quantum dots (QDs) were used as the proper sealing agents for the mesopores of HMC, conjugated to HMC via disulfide linkage to prevent drug (doxorubicin, abbreviated as Dox) premature release from Dox/HMC-SS-ZnO. After cellular endocytosis, the Dox was released in a pH, GSH and NIR laser triple stimuli-responsive manner to realize accurate drug delivery. Moreover, the local hyperthermia effect induced by NIR irradiation could promote the drug release, enhance cell sensitivity to chemotherapeutic agents, and also directly kill cancer cells. As expected, Dox/HMC-SS-ZnO exhibited a high drug loading capacity of 43%, well response to triple stimuli and excellent photothermal conversion efficiency η of 29.7%. The therapeutic efficacy in 4T1 cells and multicellular tumor spheroids (MCTSs) demonstrated that Dox/HMC-SS-ZnO + NIR had satisfactory chemo-photothermal synergistic effect with a combination index (CI) of 0.532. The cell apoptosis rate of the combined treatment group was more than 95%. The biodistribution and pharmacodynamics studies showed its biosecurity to normal tissues and synergistic inhibition effect to tumor cells. These distinguished results indicated that the Dox/HMC-SS-ZnO nanoplatform is potential to realize efficient triple stimuli-responsive drug delivery and dual model chemo-photothermal synergistic antitumor therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Oral administration of nanoparticles is extremely limited due to the two processes of mucus permeation and epithelial absorption, which requires completely opposite surface properties of the nanocarriers. To tackle the contradiction, we developed a rational strategy to modify the surface of mesoporous carbon nanoparticles with chitosan concealed by a hydrophilic N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) layer. Probucol (PB) with the low poor permeability and solubility was loaded in optimal nanocarriers to realize the high loading efficacy and controlled release. The pHPMA polymer is a hydrophilic "mucus-inert" material, which could be dissociable from the surface of nanoparticles in the mucus, thus promoting their mucus permeation and causing exposure of chitosan in transepithelial transport. The swelling effect of chitosan under acidic conditions allowed regulation of PB release behavior. In conclusion, the mucus-permeable nanocarrier could effectively overcome multiple gastrointestinal absorption barriers and the oral bioavailability of PB-loaded HCMCN was 2.76-fold that of commercial preparation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Mesoporous carriers have been widely used to deliver anticancer drugs due to their unique characteristics. In this work, mesoporous silica nanoparticles (MSN) and mesoporous carbon nanoparticles (MCN) with substantially similar and uniform particle size, specific surface area, and pore size were prepared to compare the photothermal effect, drug loading efficiencies (LE), and drug release properties. In order to improve the dispersion stability and biocompatibility of the carriers, MSN and MCN were grafted with PEG, respectively. The NIR-induced photothermal effect results indicated that MCN had a brilliant photothermal conversion efficiency due to its strong near-infrared absorption capacity, while MSN had no photothermal conversion capability. Moreover, LE of DOX in DOX/MCN-PEG reached 36.58%, higher than that in DOX/MSN-PEG, which was ascribed to non-covalent interaction of π-π stacking and electrostatic attraction. In addition, compared to DOX/MSN-PEG, DOX/MCN-PEG had a significantly increased release rate under NIR laser irradiation due to excellent photothermal conversion capability of MCN-PEG. Furthermore, cell viability assay and cellular uptake experiment results demonstrated that DOX/MCN-PEG showed a synergistic therapeutic effect in the combination of chemotherapy and phototherapy, with a combination index (CI) of 0.238.

Synergistic therapy of chemotherapy and photothermal therapy exhibits great potential to improve the therapeutic efficiency for cancer therapy. In this study, a new biocompatible multiple sensitive drug delivery system (DDS) was synthesized by covering a polydopamine (PDA) layer on doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) via disulfide bonds (MSN-SS-PDA/DOX). PDA worked as a photothermal therapy (PTT) agent and also a gate keeper to control drug release, which was highly sensitive to pH and could prolong the residence time, simultaneously increase water solubility and biocompatibility of the nanoparticles. The DDS exhibited excellent monodispersity, redox/pH/NIR-multi-dependent release characteristics, remarkable photothermal conversion property (photothermal conversion efficiency η = 40.21%) and outstanding tumor cell synergistic killing efficiency of chemotherapy and photothermal therapy (combination index CI = 0.175). The biodistribution and pharmacodynamics experiments of MSN-SS-PDA/DOX in 4T1 tumor models indicated that MSN-SS-PDA made more DOX accumulate in tumor tissue than free DOX, extend circulation time of DOX in the body, and exhibit a significant synergistic antitumor efficacy. Meanwhile, the tumor growth was remarkably inhibited, which was much more obvious than any monotherapy effect. Thus, the novel nanoplatform presents a promising future as a drug delivery system for combination therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this study, a synthetic high-density lipoprotein (sHDL), peptide-based nanocarrier loaded with docetaxel (DTX) was constructed, against breast cancer. The thermodynamic and molecular dynamic analyses were conducted to examine the stability of nanoparticles synthesized from mimetic peptide 5 A and various types of phospholipids. Furthermore, the cellular uptake and in vivo fluorescence imaging analysis experiments, with scavenger receptor B-I (SR-BI) were carried out to examine the tumor-targeting ability of sHDL. The nanoparticles were investigated for their pharmacodynamic and cytotoxic effects to show their effectivity as anti-tumor agents. The results showed that the synthesized sHDL nanoparticles exhibited a high payload of DTX, sustained drug release properties, and excellent biocompatibility. Moreover, DTX-sHDL nanoparticles enhanced the uptake of DTX, increased the cytotoxicity against MCF-7 cells, and reduced the off-target side-effects to normal cells. Finally, experiments in 4T1 cell line-bearing mice indicate that inhibition of tumor growth by DTX-sHDL nanoparticles was superior to that of free DTX group. Thus, the sHDL nanoparticles are a promising drug delivery vehicle for improving the efficacy of anti-cancer drugs.

In this work, a multi-stimuli responsive drug delivery system (MCHP) was designed for combinational chemotherapy and photothermal therapy (PTT). Mesoporous carbon nanoparticles (MCN) with a high loading efficiency were used as near-infrared (NIR)-responsive drug carriers. Human serum albumin (HSA) was attached to the pore openings of MCN via disulfide bonds to serve as a gatekeeper due to its biocompatibility and appropriate molecular size. To improve the dispersity and biocompatibility, the surface of the MCN was modified with polyethylene glycol (PEG). In vitro photothermal effect results showed that MCHP exhibited a power and concentration-dependent photothermal conversion capacity and a good photothermal stability. The doxorubicin (DOX) release from the MCHP/DOX system exhibited NIR/pH/reduction-responsive release properties. A cytotoxicity assay demonstrated that, under NIR irradiation, the MCHP/DOX exhibited chemo-photothermal synergistic effects with a combination index (CI) of 0.643. The biodistribution of DOX in vivo indicated that an NIR laser can prolong the retardation time of DOX in tumor sites. In vivo antitumor experiments showed that MCHP/DOX with NIR irradiation had the highest tumor inhibition rate against 4T1 tumors in mice. This work suggested that MCHP could be explored as a multi-responsive drug release platform for combinational photothermo-chemotherapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The tumor stromal microenvironments (TSM) including stromal cells and extracellular matrix (ECM) form an abominable barrier hampering nanoparticles accessibility to cancer cells, significantly compromising their antitumor effects. Herein, we report a bioinspired lipoprotein (bLP) that can induce efficient photothermia to remodel TSM and improve second bLP accessibility to cancer cells for antitumor therapy. The multiple stromal cells and ECM components in TSM are remarkably disrupted by bLP-mediated photothermal effects, which cause a 4.27-fold enhancement of second bLP accumulation in tumor, deep penetration in whole tumor mass and 27.0-fold increase of accessibility to cancer cells. Of note, this bLP-mediated TSM-remodeling to enhance cancer cell accessibility (TECA) strategy produces an eminent suppression of tumor growth and results in a 97.4% inhibition of lung metastasis, which is superior to the counterpart liposomes. The bLP-mediated TECA strategy provides deeper insights into enhancing nanoparticle accessibility to cancer cells for antitumor therapy.

"Gate" engineered mesoporous silica nanoparticles (MSN) have been extensively applied in cancer theranostics. Due to the complexity of tumor development and progression, with chemotherapy alone, it has often been difficult to achieve a good therapeutic effect. Currently, it has been shown that the combination with photothermal therapy overcomes the shortcoming of chemotherapy. In most studies, the photothermal effect has proven to accelerate drug release from nanocarriers and ablate malignant cells directly, but the influence on the intracellular fate of nanocarriers remains unknown. Herein, a lipophilic cyanine dye Cypate acting as a photothermal converting agent was conjugated on the external surface of MSN through a disulfide bond (MSN-Cy) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) was coated on the outside of the MSN-Cy via a hydrophobic interaction (TCMSN) to cover the pores, preventing drug preleakage in the circulation. The TCMSN underwent exocytosis through the lysosome-mediated pathway. Moderate heat induced by near-infrared light promoted lysosome disruption, which thus partly inhibited lysosome-mediated particle exocytosis. In the meantime, TPGS, as a P-glycoprotein inhibitor, blocked the drug efflux. This research elaborated the photothermal effect from a new perspective-inhibiting particle exocytosis. The as-designed "gate" engineered MSN realized a double inhibition of drug efflux and particle exocytosis from cancer cells, thus sustaining the drug action time and enhancing the antitumor activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In this research, a novel method was used to successfully stably coat Pluronic P123 on mesoporous silica nanoparticles (MSNs). Co-constructing a drug delivery system (DDS) with P123 and MSNs has not been previously reported. In this DDS, the coating of P123 was realized through a hydrophobic interaction with octadecyl chain-modified MSNs. The experiments found only Pluronic with an appropriate ratio of hydrophilic and lipophilic segments could keep the nanoassemblies stable. For comparison, nanoassemblies consisting of P123 and octadecyl chain-modified MSNs with or without a disulfide bond were prepared, which were denoted as PSMSNs and PMSNs, respectively. The disulfide bond was expected to endow the system with redox-responsiveness to enhance the therapeutic effect meanwhile decreasing the toxicity. A series of experiments including characterization of the nanoparticles, in vitro drug release, cell uptake and cellular drug release, in vitro cytotoxicity, cell migration and biodistribution of the nanoparticles were carried out. Compared with the PMSNs, PSMSNs displayed a redox-responsive drug release property not only in in vitro release text, but also on the cellular level. In addition, the cell migration experiments proved that the coating of P123 endowed the system with the ability of anti-metastasis. The accumulation of P123 in the tumor was enhanced after coating the MSNs by virtue of the 'EPR' effect of nanoparticles compared with the solution form.

Thermochemotherapy exhibits a synergistic therapeutic efficiency for cancer, and the sensitivity of cancer cells to chemical drugs could be increased to a large extent at elevated temperature. In this work, a biocompatible nanocomposite thermosensitive mesoporous carbon nanoparticles (TSMCN) was prepared by covering a liposome on mesoporous carbon nanoparticles (MCN). The TSMCN had good photothermal efficiency and photostability. The doxorubicin (DOX)-loaded TSMCN (DOX/TSMCN) showed a slower release than the DOX-loaded MCN-COOH (DOX/MCN-COOH) both in simulated tumor environment and physiological environment. And release curves of DOX/TSMCN exposed to NIR laser exhibited the fast release property. The confocal laser scanning microscopy results illustrated that cellular uptake of DOX for DOX/TSMCN can be enhanced by NIR laser. The temperature of the tumor site reached up to 51.9 °C within 3 min after exposure to laser at 1.25 W/cm 2 power density, which is above the phase transition temperature ( T m ) of liposome (40.7 °C). The biodistribution of DOX in vivo indicated that NIR laser can prolong the retardation time of DOX in the tumor site. The results of both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and antitumor efficiency elucidated that the DOX/TSMCN under NIR irradiation had a synergistic therapeutic effect for cancer. Thus, the TSMCN could be explored as a powerful nanoplatform that shows great prospect in thermochemotherapy of tumor therapy.

In recent years, multifunctional nanoparticles have attracted much research interest in various biomedical applications such as biosensors, diagnosis, and drug delivery systems. In this study, we report an NIR imaging diagnosis and therapy nanoplatform which is developed by complexing upconversion nanoparticles (UCNP@OA) NaLuF4:Er3+,Yb3+ with nanographene oxide (NGO). The obtained nanocomposites UCNP@NGO showed excellent stability and low cell toxicity, which not only acted as upconversion luminescence (UCL) probes for tumor imaging, but also served as therapy agents by converting laser energy into thermal energy for photothermal therapy (PTT) with high photothermal conversion efficiency. This work highlights the potential of UCNP@NGO nanocomposites as an integrated theranostic nanoplatform for the UCL image combinatorial PTT of cancer, providing a promising candidate for clinical antitumor treatments.

The surface chemistry and size of nanoparticles can greatly impact their interaction with biological pathways and alter efficacy. However, the interplay between surface modification and particle size has not been well investigated especially for oral delivery. It is necessary to maximize the bioavailability of loading therapeutics. Here, we prepared different sized mesoporous silica nanoparticles (100-500 nm) and conjugated them with polyethylenimine-coated carbondots (PCD) for effective transepithelial absorption. The nanoparticles were also coated with polyethylene glycol (PEG) polymers for improved mucus permeability. These mesoporous silica nanoparticles conjugated to PCD and coated in PEG (MSN@PCD@PEG) were used to study the influence of particle size and surface chemistry on transepithelial transport and bioavailability. Results demonstrated that the MSN@PCD@PEG with a diameter 250 nm had the highest transepithelial transport and oral bioavailability compared to other formulations. Drug release, endocytosis pathways, transepithelial transport and degradation of these different nanocarriers were systematically studied in order to investigate effects of size variety. The findings indicated that nanoparticle-based oral drug delivery can be potentially improved by adjusting physicochemical properties. We believe that understanding the importance of surface chemistry and particle size in the oral delivery will improve nanoparticle engineering and oral application., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Oral administration of nanocarriers remains a significant challenge in the pharmaceutical sciences. The nanocarriers must efficiently overcome multiple gastrointestinal barriers including the harsh gastrointestinal environment, the mucosal layer, and the epithelium. Neutral hydrophilic surfaces are reportedly necessary for mucus permeation, but hydrophobic and cationic surfaces are important for efficient epithelial absorption. To accommodate these conflicting surface property requirements, we developed a strategy to modify nanocarrier surfaces with cationic cell-penetrating peptides (CPP) concealed by a hydrophilic succinylated casein (SCN) layer. SCN is a mucus-inert natural material specifically degraded in the intestine, thus protecting nanocarriers from the harsh gastric environment, facilitating their mucus permeation, and inducing exposure of CPPs after degradation for further effective transepithelial transport. Quantum dots doped hollow silica nanoparticles (HSQN) with a diameter around 180 nm was used as the nanocarrier and demonstrated as high as 50% loading efficacy of paclitaxel, a model drug with poor solubility and permeability. The dual layer modification strategy prevented premature drug leakage in stomach and maintained high mucus permeation (the trajectory spanned 9-fold larger area than single CPP modification). After intestinal degradation of SCN by trypsin, these nanocarriers exhibited strong interaction with epithelial membranes and a 5-fold increase in cellular uptake. Significant transepithelial transport and intestinal distribution were also observed for this dual-modified formulation. A pharmacokinetics study on the paclitaxel-loaded nanocarrier found 40% absolute bioavailability and 7.8-fold higher AUC compared to oral Taxol®. Compared with single CPP modified nanocarriers, our formulation showed increased in vivo efficacy and tumor accumulation of the model drug with negligible intestinal toxicity. In summary, sequential modification with CPP and SCN layers on HSQN offers a potential strategy to overcome the multiple barriers of the gastrointestinal tract., Statement of Significance: Oral administration of nanocarriers remains a big challenge due to the multiple gastrointestinal barriers. In order to achieve both strong mucus permeation and efficient epithelial absorption, we modified the surface of silica nanoparticles with two layers: cell penetrating peptide (CPP) layer and succinylated casein (SCN) layer. The newly developed nanoformulations are demonstrated to have the following advantages: 1) versatile carrier with easy preparation, 2) high drug loading especially for poor soluble molecules, 3) reduced drug leakage in the stomach, 4) effective mucus penetration and transepithelial transport and 5) good biocompatibility, which in all indicate a great potential of this bilayer-modification strategy to facilitate the oral delivery of therapeutic agents., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In this paper, a redox-triggered drug delivery system of DOX/MSN-Au was prepared for chemo-photothermal synergistic therapy. The ultra-small gold nanoparticles (NPs) were appended to the openings of mesoporous silica nanoparticles (MSN) by Au-S bonds as the gatekeepers. Meanwhile, the gold NPs could be heated to high temperature by the near infrared (NIR) light irradiation, which is conducive to photothermal therapy. X-ray photoelectron spectroscopy (XPS) and Fourier Transform Infrared Spectrometer (FT-IR) spectra confirmed the formation of MSN-SH and MSN-Au. An in vitro NIR-induced photothermal study indicated that MSN-Au possessed concentration-dependent and power-dependent photothermal conversion capacity. Doxorubicin (DOX) was selected as the model drug loaded in the MSN. In vitro drug release showed that DOX released faster in the presence of glutathione (GSH) or NIR laser irradiation than without GSH or NIR irradiation, which suggested that the system had potentials for redox-responsive and NIR-triggered drug release. Confocal Laser Scanning Microscope (CLSM) was performed to evaluate the cellular uptake performance of DOX/MSN-Au. The cytotoxicity assay indicated that DOX/MSN-Au had a synergistic therapeutic effect by the combination of chemotherapy and photothermal therapy. This work suggested that MSN-Au could be explored as a redox-triggered drug delivery system for the chemo-photothermal synergistic therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A distinctive and personalized nanocarrier is described here for controlled and targeted antitumor drug delivery and real-time bioimaging by combining a redox/enzyme dual-responsive disulfide-conjugated carbon dot with mesoporous silica nanoparticles (MSN-SS-CD HA ). The carbon dot with controlling and targeting abilities was prepared through a polymerizing reaction by applying citric acid and HA as starting materials (named CD HA ). The as-prepared MSN-SS-CD HA exhibited not only superior photostability and excellent biocompatibility, but also the ability to target A549 cells with overexpression of CD44 receptors. Upon loading the antitumor drug, doxorubicin (DOX), into the mesoporous channels of MSN nanoparticles, CD HA with a diameter size of 3nm completely blocked the pore entrance of DOX-encapsulated MSN nanoparticles with a pore size of about 3nm, thus preventing the premature leakage of DOX and increasing the antitumor activity until being triggered by specific stimuli in the tumor environment. The results of the cell imaging and cytotoxicity studies demonstrated that the redox/enzyme dual-responsive DOX-encapsulated MSN-SS-CD HA nanoparticles can selectively deliver and control the release of DOX into tumor cells. Ex vivo fluorescence images showed a much stronger fluorescence of MSN-SS-CD HA -DOX in the tumor site than in normal tissues, greatly facilitating the accumulation of DOX in the target tissue. However, its counterpart, MSN-SH-DOX exhibited no or much lower tumor cytotoxicity and drug accumulation in tumor tissue. In addition, MSN-SS-CD was also used as a control to investigate the ability of MSN-SS-CD HA to target A549 cells. The results obtained indicated that MSN-SS-CD HA possessed a higher cellular uptake through the CD44 receptor-mediated endocytosis compared with MSN-SS-CD in the A549 cells. Such specific redox/enzyme dual-responsive targeted nanocarriers are a useful strategy achieving selective controlled and targeted delivery of therapeutic reagents with real-time bioimaging, and may also facilitate the development of drug delivery systems for a number of clinical applications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In recent years, spherical nanoparticles has been studied extensively on biomedical applications including bioimaging and biosensing, diagnostics and theranostics, but the effect of the shape of nanoparticles has received little attention. In the present study, we designed three different shaped fluorescent mesoporous silica nanoparticles (MSNs), long rod nanoparticles (NLR), short rod nanoparticles (NSR), and spherical nanoparticles (NS) to systematically examine their behavior in vivo after oral administration. The results of the ex vivo optical imaging study in mice indicated that rod nanoparticles had a longer residence time in the gastrointestinal compared with spherical nanoparticles. The in vivo biodistribution showed that all the orally administered MSNs were mainly taken up by the liver, and kidney. NLR had a great capacity to overcoming rapid clearance by the RES and exhibited a longer circulation in the blood than NSR and NS. During renal excretion, the spherical nanoparticles were cleared faster than rod nanoparticles. In addition, it was also found that MSNs can be degraded in vivo and NSR were degraded faster than NLR and NS probably owing to their higher specific surface area. The pharmacokinetic results demonstrated that nifedipine(NI)-loaded NLR had a higher bioavailability than NI-loaded NSR and NS.

In this study, hollow mesoporous carbon nanoparticles (HMCN) and mesoporous carbon nanoparticles (MCN) were used as near-infrared region (NIR) nanomaterials and drug nanocarriers were prepared using different methods. A comparison between HMCN and MCN was performed with regard to the NIR-induced photothermal effect and drug loading efficiency. The results of NIR-induced photothermal effect test demonstrated that HMCN-COOH had a better photothermal conversion efficacy than MCN-COOH. Given the prominent photothermal effect of HMCN-COOH in vitro, the chemotherapeutic drug DOX was chosen as a model drug to further evaluate the drug loading efficiencies and NIR-triggered drug release behaviors of the nanocarriers. The drug loading efficiency of DOX/HMCN-COOH was found to be up to 76.9%, which was higher than that of DOX/MCN-COOH. In addition, the use of an 808nm NIR laser markedly increased the release of DOX from both carbon carriers in pH 5.0 PBS and pH 7.4 PBS. Cellular photothermal tests involving A549 cells demonstrated that HMCN-COOH had a much higher photothermal efficacy than MCN-COOH. Cell viability experiments and flow cytometry were performed to evaluate the therapeutic effect of DOX/HMCN-COOH and the results obtained demonstrated that DOX/HMCN-COOH had a synergistic therapeutic effect in cancer treatment involving a combination of chemotherapy and photothermal therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this paper, a smart nanocarrier (MSNs-SS-CDPAA) is developed for redox-responsive controlled drug delivery and in vivo bioimaging by grafting fluorescent carbon dots to the surface of mesoporous silica nanoparticles (MSNs) via disulfide bonds. The polyanion polymer poly(acrylic acid) (PAA) was used to prepare the carboxyl-abundant carbon dots (CDPAA) by hydrothermal polymerization. The negatively charged CDPAA were anchored to the openings of MSNs containing the disulfide bonds through amidation and were used as gatekeepers for trapping the drugs within the pores. The in vitro release results indicated that the prepared MSNs-SS-CDPAA/DOX showed highly redox-responsive drug release in pH 7.4 and pH 5.0 PBS. In addition, the redox-responsive release mechanism was studied by measurement of the Zeta potential and fluorescence spectrophotometry. The prepared MSNs-SS-CDPAA exhibited excellent biocompatibility and fluorescence properties. Confocal laser scanning microscopy (CLSM) showed that MSNs-SS-CDPAA could emit blue, green and red fluorescence at an excitation wavelength of 408, 488 and 561nm, respectively. In addition, MSNs-SS-CDPAA/DOX exhibited a high cellular uptake as shown by CDPAA imaging and a therapeutic effect on cancer cells by MTT assay. This study describes a novel strategy for simultaneously controlled drug delivery and real-time imaging to track the behavior of nanoparticles during tumor therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In this paper, hyaluronic acid (HA) functionalized uniform mesoporous carbon spheres (UMCS) were synthesized for targeted enzyme responsive drug delivery using a facile electrostatic attraction strategy. This HA modification ensured stable drug encapsulation in mesoporous carbon nanoparticles in an extracellular environment while increasing colloidal stability, biocompatibility, cell-targeting ability, and controlled cargo release. The cellular uptake experiments of fluorescently labeled mesoporous carbon nanoparticles, with or without HA functionalization, demonstrated that HA-UMCS are able to specifically target cancer cells overexpressing CD44 receptors. Moreover, the cargo loaded doxorubicin (DOX) and verapamil (VER) exhibited a dual pH and hyaluronidase-1 responsive release in the tumor microenvironment. In addition, VER/DOX/HA-UMCS exhibited a superior therapeutic effect on an in vivo HCT-116 tumor in BALB/c nude mice. In summary, it is expected that HA-UMCS will offer a new method for targeted co-delivery of drugs to tumors overexpressing CD44 receptors.

Theranostic nanomedicine has emerged as a promising modality for cancer diagnosis and treatment. In this study, we report the fabrication of fluorescence gold nanoclusters (GNC) conjugated with a cisplatin prodrug and folic acid (FA) (FA-GNC-Pt) for fluorescence imaging and targeted chemotherapy of breast cancer. The physio-chemical properties of FA-GNC-Pt nanoparticles are thoroughly characterized by fluorescence/UV-Vis spectroscopic measurement, particle size and zeta-potential examination. We find that FA-modification significantly accelerated the cellular uptake and increased the cytotoxicity of GNC-Pt nanoparticles in murine 4T1 breast cancer cells. Fluorescence imaging in vivo using 4T1 tumor bearing nude mouse model shows that FA-GNC-Pt nanoparticles selectively accumulate in the orthotopic 4T1 tumor and generate strong fluorescence signal due to the tumor targeting effect of FA. Moreover, we demonstrate that FA-GNC-Pt nanoparticles significantly inhibit the growth and lung metastasis of the orthotopically implanted 4T1 breast tumors. All these data imply a good potential of the GNC-based theranostic nanoplatform for fluorescence tumor imaging and cancer therapy.

Hybrid mesoporous silica nanoparticles (MSNs) modified with polymer polyethylene glycol (PEG) through the biodegradable disulfide bonds were prepared to achieve 'on demand' drug release. In this system, PEG chains were chosen as the representative gatekeepers that can block drugs within the mesopores of MSNs. After the addition of glutathione (GSH), the gatekeepers were removed from the pore outlets of MSNs, followed by the release of encapsulated drugs. In this research, the effects of grafting density of gatekeepers on the drug release and biocompatibility of silica carriers were also investigated. First, PEG modified MSNs were prepared by the condensation reaction between the carboxyl groups of MSN and the hydroxyl of PEG. The structure of the resultant MSN-SS-PEG was characterized by transmission electron microscopy (TEM), nitrogen adsorption/desorption isotherms analysis and Fourier transform infrared spectroscopy (FTIR). Rhodamine B (RhB) as the model drug was loaded into MSNs. The in vitro assay results indicated that RhB was released rapidly after the addition of 10 mM GSH; M1-SS-PEG had the best capping efficiency compared with M0.5 and M1.5 groups. Moreover, hemolysis assay, serum protein adsorption and cell viability test indicated that with the increase of PEG grafting density, the biocompatibility of silica carriers increased., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Polymer-functionalized carbon nanoparticles hold great promise for their use in enhancing the oral absorption of drugs with poor oral bioavailability. And since the abundant expression of folate receptors in intestinal tract, folic acid (FA) modified uniform mesoporous carbon spheres (UMCS) was used to improve oral absorption of paclitaxel, a chemotherapeutic drug with poor oral bioavailability. In this research, folate-polyethyleneimine (FA-PEI) was grafted onto acid-treated uniform mesoporous carbon spheres through one-step electrostatic attraction. PTX was loaded into mesopores of nanoparticles through solvent evaporation, present as amorphous. The release of PTX from the FA-PEI-UMCS nanoparticles exhibited an initial rapid release, followed by a sustained release. And release rate could be regulated by changing amount of FA-PEI complex on the UMCS. The uptake of PTX-encapsulated nanoparticles was studied exploiting Caco-2 cells as an in vitro model. The results of confocal microscopy and flow cytometry demonstrated that folate functionalization enhanced internalization of nanoparticles by the cells. Moreover, PTX loaded in FA-PEI-UMCS nanoparticles resulted in a 5.37-fold increase in apparent permeability (Papp) across Caco-2 cell monolayers compared to Taxol(®). And the in vivo results showed that FA-PEI-UMCS nanoparticles did not only improve the oral bioavailability of PTX, but also decrease the gastrointestinal toxicity of PTX. In conclusion, the FA-PEI-UMCS nanoparticles might be a potentially applicable system to improve oral absorption of drugs with poor oral bioavailability., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cyclodextrin (CD)-capped mesoporous silica nanoparticles (MSN) with pH-responsive properties were synthesized, but little research has been carried out to evaluate the impact of critical factors such as the stalk density and the type of CD on the pH-responsive release behavior. Here, the effect of different stalk densities on the pH-responsive release behavior was investigated. Either too low or too high density of the grafted p-anisidine stalk could result in poor cargo release, and the optimum stalk density for MSN was measured by thermal analysis, and found to be approximately 8.7 stalks nm(-2). To achieve effective release control, the CD capes, α-CD and β-CD, were also investigated. Isothermal titration calorimetry (ITC) analysis was employed to determine the formation constants (Kf) of the two CD with p-anisidine at different pH values. The results obtained showed that the complex of β-CD with p-anisidine had excellent pH-responsive behavior as it exhibited the largest changed formation constant (ΔKf) in different pH media. Furthermore, the pH-responsive mechanism between CD and p-anisidine molecules was investigated through ITC and a molecular modeling study. The release of antitumor drug DOX presents a significant prospect toward the development of pH-responsive nanoparticles as a drug delivery vehicle.

Novel multifunctional porous titanium dioxide (TiO2) nanoparticles modified with polyethylenimine (PEI) were developed to explore the feasibility of exploiting the photocatalytic property of titanium dioxide to achieve ultraviolet (UV) light triggered drug release. Additionally, in order to further realize targeting delivery, folic acid, which chemically conjugated to the surface of the functionalized multifunctional porous TiO2 nanoparticles through amide linkage with free amine groups of PEI, was used as a cancer-targeting agent to effectively promote cancer-cell-specific uptake through receptor-mediated endocytosis. And a typical poorly water-soluble anti-cancer drug, paclitaxel, was encapsulated in multifunctional porous TiO2 nanoparticles. The PEI on the surface of multifunctional porous TiO2 nanoparticles could effectively block the channel to prevent premature drug release, thus providing enough circulation time to target cancer cells. Following UV light radiation, PEI molecules on the surface were cut off by the free radicals (OH˙ and O2-) that TiO2 produced, and then the drug loaded in the carrier was released rapidly into the cytoplasm. Importantly, the amount of drug released from multifunctional porous TiO2 nanoparticles can be regulated by the UV-light radiation time to further control the anti-cancer effect. This multifunctional porous TiO2 nanoparticle exhibits a combination of stimuli-triggered drug release and cancer cell targeting. The authors believe that the present study will provide important information for the use of porous TiO2 nanomaterials in light-controlled drug release and targeted therapy., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In the past decade, mesoporous silica nanoparticles (MSNs) with a large surface area and pore volume have attracted considerable attention for their application in drug delivery and biomedicine. In this review, we highlight the recent advances in silica-assisted drug delivery systems, including (1) MSN-based immediate/sustained drug delivery systems and (2) MSN-based controlled/targeted drug delivery systems. In addition, we summarize the biomedical applications of MSNs, including (1) MSN-based biotherapeutic agent delivery; (2) MSN-assisted bioimaging applications; and (3) MSNs as bioactive materials for tissue regeneration., From the Clinical Editor: This comprehensive review presents recent advances in mesoporous silica nanoparticles assisted drug delivery systems, including both immediate and sustained delivery systems as well as controlled release and targeted drug delivery systems. In addition to achieving therapeutic agent delivery, imaging applications and potential use of silica NPs in tissue regeneration are also discussed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6-MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence-activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system.

Oral delivery of antigens is patient-friendly and efficient way of treating intestinal infections. However, the efficacy of oral vaccines is limited by degradation in the gastrointestinal (GI) tract and poor absorption by enterocytes and antigen-presenting cells (APC). Here we report ulex europaeus agglutinin-1 (UEA-1) conjugated poly (D,L-lactide-co-glycolide) (PLGA)-lipid nanoparticles (NP) containing a Toll-like receptor (TLR)-agonist monophosphoryl lipid A (MPL) as an oral vaccine delivery system. The uniform-sized PLGA-lipid NPs (simplified as lipid NPs) were produced by the premix membrane emulsification method. They can protect the entrapped model antigen ovalbumin (OVA) from exposure to the GI tract and release the OVA in a controlled manner. With UEA-1 and MPL modification, the UEA-MPL/lipid NPs can be effectively transported by M-cells and captured by mucosal dendritic cells (DCs). After in vivo vaccination, the OVA-UEA-MPL/lipid NPs stimulated the most effective mucosal IgA and serum IgG antibodies during the oral formulations. These results suggest that this MPL containing M-cell targeted lipid NP can potentially be used as a universally robust oral vaccine delivery system., (Copyright © 2014. Published by Elsevier B.V.)

Purpose: A novel mesocellular carbon foam (MSU-FC) with a large pore size and a three-dimensional porous structure for the oral delivery of poorly water-soluble drugs was prepared. The goal of this study was to improve in vitro dissolution and in vivo absorption of celecoxib (CEB), a model drug, by means of novel carbon-based nanoparticles prepared from the MSU-FC matrix., Methods: The MSU-FC matrix was synthesized by an inverse replica templating method using mesocellular silica template. A solvent immersion/evaporation method was used to load the drug molecules. The drug-loaded nanoparticles were characterized for morphology, surface area, particle size, mesoporous structure, crystallinity, solubility and dissolution. The effect of MSU-FC on cell viability was measured using the MTT conversion assay. Furthermore, the oral bioavailability of CEB-loaded MSU-FC in fasted rats was compared with that of the marketed product., Results: Our results demonstrate that CEB incorporation into the prepared MSU-FC resulted in an approximately 9-fold increase in aqueous solubility in comparison with crystalline CEB. MSU-FC produced accelerated immediate release of CEB in comparison with crystalline CEB (pure CEB powder or marketed formulation) and the drug-loaded conventional mesoporous carbon particles. The relative bioavailability of CEB for CEB-loaded MSU-FC was 172%. In addition, MSU-FC nanoparticles exhibited very low toxicity., Conclusions: The MSU-FC nanomatrix has been shown to be a promising drug delivery vehicle for improving the dissolution and biopharmaceutical characteristics of poorly water-soluble drugs.

This study intended to develop nimodipine (NMD) nanocrystals with different sizes for oral administration and to investigate the relationship between dissolution and pharmacokinetics for NMD nanocrystals and Nimotop(®). NMD nanocrystals were prepared by combination of microprecipitation and high pressure homogenization and were further lyophilized. The particle size, morphology and aqueous solubility of the NMD nanocrystals were determined. With Nimotop(®) as the control, the dissolution rate was evaluated and the pharmacokinetic study was undertaken in beagle dogs. NMD nanocrystals with mean diameters of about 159.0, 503.0 and 833.3 nm were prepared, respectively. The lyophilization didn't affect the particle sizes of the redispersed nanocrystals. The aqueous solubility was significantly improved and displayed a size-dependent manner. The nanocrystals exhibited lower dissolution patterns than Nimotop(®) under non-sink condition, but bioavailability of the two nanocrystals (159.0 and 833.3 nm) was equivalent, about 2.6-fold higher than Nimotop(®). In conclusion, oral nanocrystal drug delivery system was a promising strategy in improving the oral bioavailability of poorly soluble or insoluble drugs. But we could not establish a favorable in vitro in vivo correlation for NMD nanocrystals and Nimotop(®) and thus the oral absorption mechanism of the NMD nanocrystals required further study., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: We had conducted a comprehensive study on preparation, characterization and pharmacokinetics of nimodipine nanocrystals for oral administration previously, and nimodipine nanocrystals displayed lower dissolution profiles but higher bioavailability than Nimotop(®). In this study, we aimed at elucidating the reasons of unfavorable in vitro in vivo correlation for NMD nanocrystals and Nimotop(®) with a hypothesis that special oral absorption mechanism was involved in the absorption of nimodipine nanocrystals., Methods: Investigations of oral absorption mechanism of the nanocrystals were performed on everted gut sac models, lymphatically (mesenteric lymph duct) cannulated SD rats, Caco-2 cell monolayers and chylomicron flow blocking rats, respectively., Results: The permeability of nanocrystals in duodenum, ileum and colon was not superior to that of Nimotop(®), suggestive of special absorption mechanisms involved. Exudates of nanocrystals from enterocytes were detected in mesenteric lymphatic fluids using a transmission electron microscope, and the bioavailability was only about half of the control after the mesenteric lymph was blocked. The nanocrystals were taken up by enterocytes via macropinocytosis and caveolin-mediated endocytosis pathways., Conclusions: It was impossible to establish a favorable in vitro in vivo correlation for NMD nanocrystals and Nimotop(®), because portions of the nanocrystals underwent macropinocytosis and caveolin-mediated endocytosis by enterocytes as intact nanocrystal forms, then bypassed the liver first-pass metabolism., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The central purpose of this study was to evaluate the impact of drug particle size and crystalline state on valsartan (VAL) formulations in order to improve its dissolution and bioavailability. VAL microsuspension (mean size 22 μm) and nanosuspension (30-80nm) were prepared by high speed dispersing and anti-solvent precipitation method and converted into powders through spray drying. Differential scanning calorimetry studies indicated amorphization of VAL in the spray-dried valsartan nanosuspension (SD-VAL-Nano) but recrystallization occurred after 6 months storage at room temperature. The spray-dried valsartan microsuspension (SD-VAL-Micro) conserved the crystalline form. The VAL dissolution rate and extent were markedly enhanced with both SD-VAL-Micro and SD-VAL-Nano as compared to crude VAL crystals over the pH range of 1.2-6.8. Pharmacokinetic studies in rats demonstrated a 2.5-fold increase in oral bioavailability in the case of SD-VAL-Nano compared with the commercial product while the SD-VAL-Micro provided a much less desirable pharmacokinetic profile. In conclusion, reducing particle size to the nano-scale appears to be a worthwhile and promising approach to obtain VAL products with optimum bioavailability. In addition, the impact of crystalline state on the bioavailability of nano-sized VAL might be not as big as that of particle size., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A novel spherical nanosilica matrix (SNM) together with chitosan (CTS) encapsulated SNM (CTS-SNM) was developed in order to investigate the feasibility of using chitosan to regulate drug release rate from porous silica and obtain an oral sustained drug delivery system. To achieve this goal, we synthesized a spherical nanosilica matrix (SNM) and incorporated chitosan chains on the SNM surface. Solvent evaporation method was adopted to load the model drug carvedilol into SNM and CTS-SNM. The physicochemical properties of the drug carriers and drug-loaded composites were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The structural changes in CTS-SNM in simulated gastrointestinal fluid as well as the relationships between swelling effect of chitosan and in vitro drug release behaviors were investigated. Pharmacokinetic and bioavailability aspects were also discussed. The results showed that the powerful dispersing effect of SNM and the blocking action due to the swelling of chitosan were the two main factors contributing to the sustained drug release behavior. The swelling effect of chitosan in an acidic environment together with the shrinking effect in a relatively alkaline environment allowed regulation of drug release behavior in simulated gastrointestinal fluid. An in vivo study showed that the bioavailability of CAR was improved 182% compared with that of the commercial capsule when SNM was used as the drug carrier. As for CAR-CTS-SNM, the T(max) of CAR was delayed by about 3.4 h and the bioavailability was slightly increased in comparison with the commercial capsule. We believe that SNM and CTS-SNM developed in this study will help increase the use of polymers and inorganic materials in pharmaceutical applications and stimulate the design of oral drug delivery systems for immediate or sustained release of poorly water-soluble drugs.

Three different kinds of silica (S2, S1 and SBA-15) with different particle sizes (130, 430 nm and 1-2 μm) and different pore characteristics (i.e. pore size and shape) were developed as oral vaccine immunological adjuvants and the relationship between the silica architecture and immunological properties was investigated. The silica particles were characterized using SEM, TEM and nitrogen adsorption. Model antigen bovine serum albumin (BSA) was successfully entrapped into the silica pores to produce a sustained release vaccine delivery system. Compared with the responsiveness induced by parenteral administration of BSA emulsified in Freund's complete adjuvant (FCA), oral immunization with the silica/BSA formulation produced a stimulated humoral and mucosal (sIgA) response. The IgG and IgA titers induced by loading BSA was as follows: S1>S2>SBA-15. The highest IgG and IgA titers of S1 were attributed to its large honeycombed pores and the optimal particle diameter of 430 nm. The corresponding IgG1 and IgG2a titers were also investigated to confirm that BSA loaded in nanoparticles by oral immunization can induce both T-helper 1- and T-helper 2- (Th1 or Th2) mediated responses. We believe that the results of our research will open up new avenues for the formulation of oral vaccines., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Simvastatin is classified as a Biopharmaceutics Classification System (BCS) Class-II compound with a poor aqueous solubility and an acceptable permeability through biomembranes. The strategy of increasing the in vitro dissolution has the potential to enhance the oral bioavailability when using nanosized crystalline drugs., Objective: The aim of this article was to prepare simvastatin nanocrystals to enhance its dissolution rate and bioavailability by exploiting sonoprecipitation., Methods: Injecting 0.50% (w/v) methanol solution of simvastatin into 0.20% (w/v) water solution of F68 under sonication amplitude of 400 W and processing temperature of 3°C., Results: Simvastatin nanocrystal with average diameter of 360 ± 9 nm could be obtained. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) confirmed the decreased crystallinity of nanoparticles stabilized by F68. The results of in vitro study demonstrated that the saturation solubility and dissolution rate of simvastatin nanocrystals were enhanced by 1 fold and 4 fold respectively, compared with crude simvastatin and the dissolution rate improved with the decrease in particle size. The C(max) and AUC((0-24 h)) values of simvastatin nanocrystal group were approximately 1.50-fold and 1.44-fold greater than that of simvastatin nanocrystal group, respectively. Additionally, the T(max) of simvastatin nanocrystal group was 1.99 h, comparing to 2.88 h of reference group., Conclusion: Sonoprecipitation method can produce small and uniform simvastatin nanocrystals with an improved saturation solubility, dissolution rate and oral bioavailability.

We investigate the effects of spherical mesoporous silica nanoparticles (MSNs) as an oral drug delivery system to improve the oral bioavailability of the model drug telmisartan (TEL) and examine their cellular uptake and cytotoxicity. Further, we explore the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by MSNs. An investigation of intestinal epithelial cellular binding, association and uptake was carried out by laser scanning confocal microscopy, transmission electron microscopy and fluorescence activated cell sorting. The results show that the cellular uptake is highly time-, concentration- and size-dependent. The model drug permeability studies in the human colon carcinoma (Caco-2) cell lines indicated that MSNs could significantly enhance TEL permeability and reduce rate of drug efflux. After loading TEL into MSNs, its oral bioavailability was compared with that of the marketed product Micardis and TEL-loaded ordered mesoporous silica microparticles (MSMs) in beagle dogs. The relative bioavailability of TEL-loaded MSN formulation and TEL-loaded MSM formulation was 154.4 ± 28.4% and 129.1 ± 15.6%, respectively. MSNs offer the potential to achieve enhanced oral bioavailability of poorly soluble drugs via improved drug dissolution rate and enhanced drug permeability.

In the present study, we exploited for the first time the potential of 3-D ordered macroporous (3DOM) silica as matrix for drug nanoparticles, in order to obtain proper control over drug particle size in the sub-micrometer range, enhance the dissolution rate, and reduce gastric damage. 3DOM silica matrix with 3-D spherical pores of 200 nm was successfully created and then loaded with IMC nanoparticles at various drug-silica ratios. A rapid release profile for IMC nanoparticle formulations was achieved in comparison with microsized IMC and a commercial capsule, which could be attributed to both increase in the specific surface area and decrease in the crystallinity of IMC, as well as the hydrophilic surface and the interconnected pore networks of 3DOM silica. Reduced gastric damage of IMC was demonstrated, and the protective effect may arise from the reduction in drug particle size as well as encapsulation effect of 3DOM silica., (Copyright © 2011 Elsevier B.V. All rights reserved.)