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For inflammatory bowel disease (IBD) therapy, systemic exposure of anti-TNF-α antibodies brought by current clinical injection always causes serious adverse effects. Colon-targeted delivery of anti-TNF-α antibodies through the oral route is of great importance but remains a formidable challenge. Here, we reported a biomimetic nanocomposite made of a ginger-derived exosome and an inorganic framework for this purpose. A large mesoporous silicon nanoparticle (LMSN) was uniquely customized for the antibody (infliximab, INF) to load it at high levels up to 61.3 wt% and prevent its aggregation. Exosome-like nanovesicles were isolated from ginger (GE) with a high-level production (17.5 mg kg-1). Then, ultrasound was used to coat GE onto the LMSN to obtain the biomimetic nanocomposite LMSN@GE. As expected, LMSN@GE showed advantages in the oral delivery of INF: stability in the gastrointestinal tract, colon-targeted delivery and high intestinal epithelium permeability. Amazingly, GE also presented an anti-inflammatory effect by blocking the NLRP3 inflammasome in addition to its delivery value. As a result, INF/LMSN@GE showed a significantly higher efficacy in colitis mice compared to the intravenously administered INF. This work provides new insights into colon-targeted delivery of anti-TNF-α antibodies via the oral route. Moreover, it puts forward a novel strategy for drug delivery using one therapeutic agent (herb-derived exosomes).

The objective of this work is to construct a nanosuspension drug delivery system of probucol, a BCS II drug, in order to improve its dissolution and oral bioavailability. The wet milling procedure using planetary beads-milling equipment was utilized to grind the raw probucol to ultrafine nanoparticle/nanocrystal aqueous suspension that was further solidified by freeze-drying process. Cellulose derivatives of different substitution groups and molecular weights, including HPMC, HPC, and MC, were evaluated as the primary stabilizer of probucol nanosuspension. Ternary stabilizers system composed of a primary stabilizer (cellulose derivative, i.e. HPC), a nonionic surfactant (Pluronic® F68), and an anionic surfactant (SDS) was employed to obtain probucol nanosuspension of finer particle size and enhanced dissolution in aqueous media. The probucol nanosuspension with good physical stability showed no obvious change of particle size even after storing over 7 d at 4 °C or 25 °C. The solidified probucol nanosuspension with trehalose as the cryoprotectant showed the highest dissolution rate (> 60% at 2 h) compared to other cryoprotectant. The in vivo pharmacokinetic evaluation indicated about 15-folds higher AUC value of the probucol nanosuspension compared to that of coarse probucol suspension after oral administration to rats. The probucol nanosuspension prepared by wet-milling and ternary stabilizers system may find wide applications for improving the dissolution and oral absorption of water-insoluble drugs., Graphical abstract The wet milling procedure using planetary beads-milling equipment was utilized to grind the raw probucol to ultrafine nanoparticle/nanocrystal aqueous suspension that was further solidified by freeze-drying process. Image, graphical abstract

In this work, a tumor-targeted and multi-stimuli responsive drug delivery system combining infrared thermal imaging of cells with thermo-chemotherapy was developed. Oxidized mesoporous carbon nanoparticles (MCNs-COOH) with high photothermal conversion ability (photothermal transduction efficiency η = 27.4%) in near-infrared (NIR) region were utilized to encapsulate doxorubicin (DOX). The outer surfaces of MCNs-COOH were capped with multifunctional carbon dots (CDHA) as simultaneous smart gatekeepers, a tumor targeting moiety and a fluorescent probe. NIR laser irradiation killed cancer cells through NIR-light induced hyperthermia, facilitated chemotherapeutic drug release and enhanced the sensitivity of tumor cells to drugs. The therapeutic efficacy in two-dimensional (2D) and three-dimensional (3D) cells demonstrated that MC-CDHA loading DOX (MC-CDHA/DOX) had good chemo-photothermal synergistic antitumor effects (combination index of CI = 0.448). The biodistribution and pharmacodynamics experiments of MC-CDHA/DOX in the 4T1 tumor model indicated that MCNs-COOH prolonged the residence time of DOX in tumor tissues and therefore actualized effective synergistic photothermal chemotherapy. By combining these excellent capabilities, the tumor-targeted and multi-stimuli responsive drug delivery system can be utilized as a visible nanoplatform for chemophotothermal synergistic therapy.

Glutamic acid modified Pluronic P123 (P123-G) was synthesized to coat hydrophobic mesoporous silica nanoparticles (PGMSN) aiming to target large amino acid transporter 1 (LAT1) overexpressed cancer cells. We discovered that, once internalized, PGMSN could be transported out of the cells with their cargo, and the exported nanoparticles were then taken up by neighboring cells. This intercellular delivery of particles led to a deeper tumor penetration, presumably through tandem cycles of LAT1 mediated endocytosis and exocytosis. Taking advantage of high drug loading capability of MSN, a kind of cyanine dye Cypate acting as a photothermal converting agent was loaded into MSN along with the chemotherapeutic drug doxorubicin hydrochloride (DOX) to improve the anti-cancer effect by the combination of chemotherapy and photothermal therapy (PTT). Both DOX and Cypate stably dispersed in the pores of MSN, and the coating of P123-G serving as diffusion barrier blocked drug preleakage. The system possessed pH and near-infrared (NIR) light dual-responsive DOX release property. Additionally, PGMSN exhibited targeted PTT effect which strengthened cytotoxic activity of the system due to the enhanced endocytosis. So the deep tumor penetration and targeted PTT effect made PGMSN especially suitable for cancers overexpressing LAT1 receptors.

Mesoporous silica cocoon materials (MSNCs) and MgO doped mesoporous silica cocoons (MgO-MSNCs) with the cocoon-like hierarchical morphology and different alkalinities were synthesized as carriers for acidic drugs. Indomethacin (IMC) was selected as a model drug and loaded into carriers. All materials and the drug-loaded samples were characterized by nitrogen adsorption, FTIR spectroscopy, transmission electron microscopy (TEM), powder X-Ray diffraction (XRD) and differential scanning calorimetry (DSC). The effect of the Mg/Si molar ratio on the kinetics and equilibrium of IMC adsorption on MgO-MSNCs was thoroughly examined, and it was found that the increase in the Mg/Si molar ratio resulted in an increasing IMC adsorption rate due to the increased affinity between alkaline MgO-MSNCs and weak acid IMC. The adsorption kinetics fitted a pseudo second-order model well. The Freundlich isotherm showed a better fit, indicating that the coverage of IMC on the surface of MgO-MSNCs was heterogeneous. The maximum adsorption capacity of adsorbent was calculated by the Langmuir isotherm equation. The Temkin equation provided further support that the IMC adsorption on MgO-MSNCs was dominated by a chemisorption process. MgO-MSNCs also have the advantage of allowing an adjustment of the drug release rate of weak acid drug. The cytotoxicity assay indicated good biocompatibility of MgO-MSNCs. Our research on MgO-MSNCs carriers demonstrated their potential therapeutic benefit for safe and effective management of IMC adsorption and in vitro release., Graphical abstract Image, graphical abstract

Ying Zhang,1 Tianfu Zhou,1 Jian Li,1 Nuo Xu,1 Mingze Cai,1 Hong Zhang,2 Qinfu Zhao,3 Siling Wang3 1Key Laboratory of TargetDrug Design and Research, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China; 2Van ’T Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, 1098 XH, the Netherlands; 3Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of ChinaCorrespondence: Qinfu Zhao; Siling Wang Tel/Fax +86 24 43520555Email qinfuzhao@syphu.edu.cn; silingwang@syphu.edu.cnIntroduction: Aim to obtain a NO donor that can control released NO in vivo with the high efficacy of tumor suppression and targeting, a nanoplatform consisting of FA-Fe3O4@mSiO2-Au/DOX was constructed.Methods: In vitro, the nanoplatform catalyzed NO’s release with the maximum value of 4.91 μM within 60 min at 43°C pH=5.0, which was increased by 1.14 times when the temperature was 37°C. In vivo, 11.7 μg Au in the tumor tissue was found to catalyze S-nitrosoglutathione continuously, and 54 μM NO was checked out in the urine.Results and Discussion: The high concentration of NO was found to increase the apoptotic rate and to reduce tumor proliferation. In the chemo-photothermal combination therapy, the tumor inhibition rate was increased up to 94.3%, and Au’s contribution from catalyzing NO release NO was 8.17%.Keywords: thermotherapy, chemotherapy, NO control release, magnetic mesoporous silica nanocomposites

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 1O2 generation upon light exposure, which not only initiate immediate disassembly of AlP/CPT-NPs but also promote cytoplasmic delivery of CPT through 1O2-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 1O2 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.

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.

Cancer stem-like cells (CSCs) are proposed to be responsible for tumor metastasis, resistance and relapse after therapy, but are unable to be eliminated by many current therapies. Herein, we report that the apoferritin nanocages loading cytotoxic mertansine (M-AFN) can significantly improve their uptake in CSCs-enriched tumorspheres and effectively eradicate CSCs in tumorspheres for anticancer therapy. M-AFN were uniformly nanocage structures with the mean diameter of 11.26 ± 2.58 nm and the loading capacity of 0.62%. In the CSCs-enriched tumorsphere model, M-AFN could be preferentially internalized by tumorsphere cells and the average half-inhibitory concentration (IC50) of M-AFN was obviously reduced by 5.46-fold when comparing to the parent 4T1 breast cancer cells. Moreover, both the already existing tumorspheres and the formation of secondary tumorspheres were drastically disrupted by M-AFN, but barely impacted by mertansine alone. The flow cytometer analysis showed the CSCs fractions in tumorspheres were considerably reduced by the M-AFN treatment. Therefore, the apoferritin nanocages represent an encouraging nanoplatform to eradicate CSCs for effective anticancer therapy.

To improve the corneal permeability and water-solubility of disulfiram (DSF), which is an ocular drug for cataract, P188 was selected as a matrix to prepare solid dispersion of DSF (DSFSD) by hot melt method. The DSFSD was characterized by DSC, XRD, and IR, and the results suggested that DSF was amorphous in DSFSD. The DSFSD was added to borate buffer solution (BBS) contained 20% poloxamer P407 and 1.2% poloxamer P188 to form in-situ gel. In vitro and in vivo experiments revealed that DSFSD combined with in-situ gel (DSFSD/in-situ gel) increased the residence time and the amount of DSF penetrated through the corneal. The pharmacodynamics studies exhibited DSFSD/in-situ gel delayed the development of selenium-induced cataract at some content. These results investigated that DSFSD/in-situ gel as a drug delivery system can improve DSF ocular permeability., Graphical abstract Disulfiram solid dispersion was prepared by hot melt method. DSFSD/in-situ gel was also prepared through adjustment of the ratio of P407 to the P188, in-situ gel turned into semisolid at the temperature around eye and then covered the corneal. Which could increase the residence time and the amount of DSF penetrated through the corneal.Image, graphical abstract

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 carbon dots (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.

In this manuscript, the effect of the particle size of polymer-functionalized mesoporous carbon (MPP) nanoparticles on enhancing oral absorption of a water-insoluble drug is first investigated. The insoluble drug, fenofibrate (Fen), was selected as the model drug loaded in the MPP nanoparticles. MPP nanoparticles with different particle sizes were designed for improving the oral bioavailability of drugs, in which the branched polyethyleneimine (PEI) and polyacrylic acid (PAA) were modified on the surfaces of mesoporous carbon nanoparticles (MCNs) with amide bonds. In addition, PEI-functionalized carbon quantum dots (PCA) and radioisotope 125I were applied to label the MPP nanoparticles to trace in the vivo process. According to the data, the MPP nanoparticles could markedly improve the dissolution rate and oral bioavailability of Fen. Interestingly, the MPP nanoparticle size had a notable effect on Fen oral absorption, and intermediate sized MPP nanoparticles were expected to be more ideal oral drug carriers. The nanoparticles were safe and easily excreted. These findings present the prospect of MPP nanoparticles for oral application, and guides the rational design of an oral delivery system with respect to particle size.

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.

The purpose of the study was to design a novel octa-arginine (R8) modified lipid emulsion (LE) system for the ocular delivery of the lipophilic drug disulfiram (DSF). The influence of the particle size of the lipid emulsions and the presence of R8 on corneal permeation was studied. DSF-loaded lipid emulsions with different particle sizes (DSF-LE1, DSF-LE2, DSF-LE3) and DSF-loaded lipid emulsions modified with R8 (DSF-LE1-R8 and DSF-LE2-R8) were prepared. The Zeta potential of the lipid emulsions was changed from negative to a positive value after modification of R8. The mucoadhesion of different preparations was investigated, and DSF-LE1-R8 was found to produce the strongest mucoadhesion. The in vitro corneal penetration study and in vivo ocular distribution study showed that the R8 modified lipid emulsion (DSF-LE1-R8) with a nano particle size, exhibited the highest permeability and the largest amount of DDC distributed in ocular issues. Coumarin-6 labelled LE1-R8 displayed more homogeneous fluorescence with the deeper penetration into the cornea compared with other preparations at various times. Confocal laser scanning microscopy showed that, in addition to paracellular routes, LE-R8 could also transport across the corneal epithelium by transcellular routes as a result of increased uptake due to the R8 modification. Furthermore, the anti-cataract effect was evaluated and it was found that DSF-LE1-R8 exhibited a marked anti-cataract effect. Therefore, the lipid emulsions with nano-sized particles and modification of R8 were proposed as a potential ocular delivery system to improve the corneal penetration and ocular delivery of DSF.

An efficient and intelligent nano-carrier that combines cell imaging with near infrared (NIR) light and redox dual-responsive drug delivery was successfully prepared. The hollow mesoporous carbon (HMC) nanoparticles with high photothermal conversion ability were developed to increase the drug loading efficiency and realize chemotherapy and photothermal synergetic therapy. The photo-stable and luminescent carbon dots (CDs) were prepared from branched polyethyleneimine (PEI) by hydrothermal reaction. The PEI CDs (CDPEI) were grafted on the openings of HMC as the "gatekeepers" via disulfide units (HMC-SS-CDPEI) to prevent the premature release of doxorubicin (DOX). In the presence of GSH, the CDPEI separated from HMC due to the breakage of disulfide bonds, thus triggering the rapid release of the encapsulated drug. In addition, the release rate of DOX could be further accelerated by NIR light irradiation due to the increased temperature which would decrease the interaction between HMC and DOX. The fluorescence of the CDPEI is quenched when being attached to the HMC, while it is recovered when the CDPEI breaking away from HMC. Hence, the fluorescent CDPEI not only act as a gatekeeper to control drug release but also play a vital role in monitoring the process of the drug delivery. The developed HMC-SS-CDPEI showed dual-responsive drug release property and could be used as visible nano-platforms for chemo-photothermal synergistic therapy.

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.

In this work, a redox and enzyme dual-stimuli responsive drug delivery system (DDS) with tracking function (HMSN-SS-CDPEI@HA) based on carbon dots capped hollow mesoporous silica nanoparticles (HMSN) has been developed for targeted drug delivery. The positively charged CDPEI nanoparticles prepared by polyethylenimine (PEI) were grafted on the pore openings of HMSN through disulfide bonds and were used as "gatekeepers" to trap the drugs within the hollow cavity. The hyaluronic acid (HA), a natural polysaccharide, was further grafted on the surface of HMSN to realize targeted drug delivery, controlled drug release and improved the stability. Doxorubicin (DOX) was chosen as a model drug due to its wide clinical application. In vitro drug release profiles demonstrated that DOX-loaded HMSN-SS-CDPEI@HA exhibited redox and enzyme dual-responsive drug release property. In addition, the prepared HMSN-SS-CDPEI@HA exhibited excellent fluorescent properties and biocompatibility. Confocal laser scanning microscope (CLSM) and flow cytometry (FCM) illustrated that HMSN-SS-CDPEI@HA exhibited a higher cellular uptake via the CD44 receptor-mediated endocytosis by CD44-receptor over-expressed A549 cells than NIH-3T3 (receptor-negative) cells, leading to higher cytotoxicity against A549 cells than NIH 3T3 cells. This work suggested an exploration of dual-stimuli responsive as well as real-time imaging targeted drug delivery system based on HMSN and the prepared HMSN-SS-CDPEI@HA could be a promising platform for cancer therapy.

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-CDHA). The carbon dot with controlling and targeting abilities was prepared through a polymerizing reaction by applying citric acid and HA as starting materials (named CDHA). The as-prepared MSN-SS-CDHA 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, CDHA 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-CDHA 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-CDHA-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-CDHA to target A549 cells. The results obtained indicated that MSN-SS-CDHA 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.

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.

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.

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., The stromal cells and extracellular matrix hamper nanoparticle access to cancer cells and their anti-cancer efficacy. Here, the authors report a bioinspired lipoprotein (bLP) for photothermal remodelling of tumour stroma and show this to improve subsequent bLP accessibility to cancer cells.

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.

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.

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.

The limited penetration of nanoparticles and their poor accessibility to cancer cell fractions in tumor remain essential challenges for effective anticancer therapy. Herein, we designed a targeting peptide-decorated biomimetic lipoprotein (termed as BL-RD) to enable their deep penetration and efficient accessibility to cancer cell fractions in a tumor, thereby improving the combinational chemo-photodynamic therapy of triple negative breast cancer. BL-RD was composed of phospholipids, apolipoprotein A1 mimetic peptide (PK22), targeting peptide-conjugated cytotoxic mertansine (RM) and photodynamic agents of DiIC18(5) (DiD). The counterpart biomimetic lipoprotein system without RM (termed as BL-D) was fabricated as control. Both BL-D and BL-RD were nanometer-sized particles with a mean diameter of less than 30 nm and could be efficiently internalized by cancer cells. After intravenous injection, they can be specifically accumulated at tumor sites. When comparing to the counterpart BL-D, BL-RD displayed superior capability to permeate across the tumor mass, extravasate from tumor vasculature to distant regions and efficiently access the cancer cell fractions in a solid tumor, thus producing noticeable depression of the tumor growth. Taken together, BL-RD can be a promising delivery nanoplatform with prominent tumor-penetrating and cancer cells-accessing capability for effective tumor therapy., Graphical abstract The deep penetration of nanoparticles in tumor and their accessibility to cancer cell fractions are essential prerequisites for effective anticancer therapy. Herein, we designed a CRGDfK peptide-decorated biomimetic lipoprotein nanoplatform (termed as BL-RD) with efficient tumor-penetrating and cancer-cell-accessing capability to improve the combinational chemo-photodynamic therapy.Image 1

Thermochemotherapy has shown a synergistic anti-cancer efficiency and can enhance the therapeutic effect of simple chemotherapy. The photothermal conversion characteristics of carriers are vital in thermo-chemotherapy. Therefore, hollow mesoporous carbon (HMC) with excellent heating efficiency and a large specific surface area was used to ensure the high loading capacity. Next, approximately 4 nm spherical gold nanoparticles (NPs) were employed as gatekeepers of the tunnels of HMC by Au-S bonds, which have the same size as HMC mesopores. Additionally, the gold NPs could avoid the premature release of the drug and enhance the photothermal properties of the delivery system. The surface of the carriers was modified with polyethylene glycol (PEG) to increase the biocompatibility and dispersity of doxorubicin (DOX) loaded DOX/HMC-Au@PEG. DOX release was markedly accelerated in the presence of glutathione (GSH) and near-infrared (NIR), indicating that the system had redox and NIR dual-triggered drug release characteristics. Cytotoxicity experiments proved that combined therapy induced the highest cell killing level. Additionally, the combination index (CI) of DOX/HMC-Au@PEG was 0.452, indicating the synergistic effect of chemotherapy and photo-thermal therapy (PTT). In vivo antitumor experiments were also carried out and showed the same trend. In general, the results of this study indicated that DOX/HMC-Au@PEG has great potential in dual-triggered drug delivery and thermochemotherapy.

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/cm2. Therefore, DOX/HMC-SS-PDA@CDs nano-platform had broad application prospects in low power therapy and convenient imaging of carbon-based materials.

In this paper, a smart nanocarrier (MSNs-SS-CD PAA ) 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 (CD PAA ) by hydrothermal polymerization. The negatively charged CD PAA 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-CD PAA /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-CD PAA exhibited excellent biocompatibility and fluorescence properties. Confocal laser scanning microscopy (CLSM) showed that MSNs-SS-CD PAA could emit blue, green and red fluorescence at an excitation wavelength of 408, 488 and 561 nm, respectively. In addition, MSNs-SS-CD PAA /DOX exhibited a high cellular uptake as shown by CD PAA 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.

To achieve GSH-responsive 5-Fluorouridine (5-FU) delivery, a novel family of nanogel drug carriers has been successfully prepared. The new class of PAHy-based nanogels was prepared by the crossing-link reaction of poly- α , β -polyasparthydrazide (PAHy) chains and 3,3′-dithiodipropionic acid (DTDPA) consisting of a redox-responsive chain network. This particle highlights recent efforts in introducing a disulfide bond to drug delivery nanogel by DTDPA, and the increased release properties of complex nanogels produced excellent glutathione (GSH)-sensitivity and significant anti-tumor therapeutic efficacy. The PAHy-based nanogels were characterized by Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS) (nano-particle size ~200 nm), UV–vis spectrometry, X-ray diffraction (XRD) and differential scanning calorimetric (DSC). PAHy-based nanogels are promising controlled-release carriers for the tumor-targeting delivery of the anticancer agent 5-Fluorouridine.

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.

Incorporation of degradable groups such as thioether bonds can make nanoparticles susceptible to be degraded by biological redox stimulus. Few studies have paid attention to effects of different surface properties of carriers on degradation behaviors between traditional mesoporous silica carriers and hybrid organosilica carriers, caused by inserted thioether groups. In this work, colloidal mesoporous silica (CMS) and hybrid colloidal mesoporous silica (HCMS) with different contents of doped thioether bonds are constructed to compare their physicochemical properties and degradability. With the increased amounts of doped thioether bonds, specific surface areas and Zeta potentials of HCMS nanoparticles decrease. Additionally, dynamic contact angle and the oil-water distribution coefficient are combined to characterize the hydrophobicity of CMS and HCMS nanoparticles. Therefore, after incorporating thioether bonds into the structure of carriers, the degradation behavior of HCMS nanoparticles in the medium were the result of weighing the advantages of degradable thioether bonds and disadvantages of decreased specific surface area and enhanced hydrophobicity of carriers. Experimental results displayed that, in the high concentration of reductive environment, HCMS carriers with doping proper proportion of thioether groups showed the fast degradation rate due to the cleaved thioether bonds as the dominant factor. The present work breaks the common views that all thioether bonds-bridged organosilica could become excellent biodegradable carriers, providing an objective perspective to evaluate the degradability of hybrid organosilica carriers.

Oral delivery of nanocarriers is exceedingly limited owing to the two speed-limited processes of epithelial absorption and mucus permeation, which demands totally opposite surface characters of nanoparticles. In order to address this contradiction, we proposed a reasonable idea about functionalizing the surface of mesoporous silica with positively charged amino groups and hydrophilic succinylated casein (SCN) polymer. Mesoporous silica nanoparticles doped with quantum dots (QMSN) with an average particle size at 160 nm were employed as the nanocarriers. Paclitaxel (PTX) with poor solubility and permeability was loaded in the nanoplatforms in a non-crystalline state to realize a relatively high drug loading efficacy of 11.9% and controlled release property. The coated SCN can hinder the premature release in gastric environment, and be specifically detachable in intestine to accelerate PTX release under the existence of trypsin, promote the mucus permeation and result in exposure of amino groups after degradation to realize efficient transepithelial transport. Compared with amino modified QMSN, QMSN-SCN showed increased intestinal uptake in vivo. Toxicity studies showed the both QMSN and QMSN-SCN had the excellent biosecurity for in vivo application. In summary, successive and easy functionalization of amino groups and SCN polymers on the surface of QMSN provide a promising strategy to conquer the multiple gastrointestinal barriers.

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.

Recent years, photothermal therapy (PTT) as a noninvasive cancer treatment has attracted wide interests of researchers worldwide. Platforms which can transform near infrared (NIR) laser power into heat play vital roles in PTT. In this paper, mesoporous carbon nanospheres (MCN) and graphene oxide nanosheets (GO), two widely used platforms in cancer treatment were compared in photothermal effect induced by NIR as well as the drug loading and release behaviors of the model drug doxorubicin (DOX). MCN and GO were grafted with polyethylene glycol (PEG) to improve the biocompatibility and aqueous stability. The elevated temperature of MCN-PEG was obviously superior to GO-PEG both in vitro and cellular photothermal effect. MCN-PEG and GO-PEG showed photothermal stability under repeated NIR irradiation. Additionally, the photothermal conversion efficiency (η) of MCN-PEG was calculated to be 32.24 %, which was higher than that of GO-PEG (27.13 %). Both nanovehicles had the similar drug loading capacities, however, the accumulative release rate of DOX/MCN-PEG was 1.6 times higher than DOX/GO-PEG in the pH 5.0 phosphate buffer solutions (PBS) exposed to NIR laser. Moreover, the cell viability assays and cellular uptake experiments validated that DOX/MCN-PEG possessed more excellent synergetic effect in chemo-photothermal therapy with the combination index (CI) of 0.443 compared with DOX/GO-PEG (0.661).

Thermo-chemotherapy could improve the therapeutic effects of single chemotherapy with the help of cytotoxic heat produced by the PTT (photothermal therapy). The photothermal conversion property of material needs to be preferentially considered in the design the drug delivery in the thermo-chemotherapy. Therefore, in this work, mesoporous carbon nanoparticles (MCN) with excellent heat generating efficiency and high surface area was designed. And the NIR absorbing dye cypate was conjugated on the surface of MCN by the cleavable disulfide bonds to hinder the premature release of doxorubicin (DOX) and enhance the photothermal properties of MCN-based delivery systems. And then TPGS was further covered on the surface of MCN by hydrophobic force to prolong circulation time and improve the biocompatibility and dispersion stability of MCN-CyT in physiological environment. The release of DOX accelerated obviously in the presence of glutathione (GSH), acidic condition and NIR irradiation, indicating that DOX/MCN-CyT exhibited redox/pH/NIR triple-triggered drug release. The anti-tumor experiment indicated that DOX/MCN-CyT showed a synergistic thermo-chemotherapy effect for cancer. Thus, the present research provides huge potential in multi-triggered drug delivery and thermochemotherapy for combination therapy.

The aim of this study was to develop a novel ocular drug delivery system based on the hydroxypropyl beta cyclodextrin (HP-β-CD) inclusion complex coated with the synthesized chitosan-N-acetyl- l -cysteine conjugate (CS-NAC) for the hydrophobic drug quercetin. The inclusion complex was prepared by the solvent evaporation method, and the concentration of HP-β-CD and CS-NAC was optimized by isolated corneal penetration test. The optimized concentration of HP-β-CD and CS-NAC was 20% (w/v) and 0.1% (w/v), respectively. The CS-NAC/quercetin-HP-β-CD had the effect on improving the ocular penetration with little ocular irritation and could increase the ocular distribution significantly. Meanwhile, Coumarin-6 (C6) labelled CS-NAC/C6-HP-β-CD possessed enhanced fluorescence and located deeper into the epithelium of cornea at the same time point compared with the uncoated one. It could also transport drug through the corneal epithelium by intracellular routes except for intercellular routes. Furthermore, it could delay the occurrence of cataract about 1 d when administrated with full-dosage quercetin. The HP-β-CD inclusion complex coated with CS-NAC is a safe and promising ocular drug delivery system for improving the bioavailability and corneal penetration of hydrophobic drug like quercetin.

Cancer stem cells (CSCs) are proposed to account for the initiation of cancer metastasis, but their accessibility remains a great challenge. This study reports deep tumor‐penetrated biomimetic nanocages to augment the accessibility to CSCs fractions in tumor for anti‐metastasis therapy. The nanocages can load photothermal agent of 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DBN) and chemotherapeutic epirubicin (EBN) to eradicate CSCs for photothermal‐chemotherapy of breast cancer metastasis. In metastatic 4T1‐indcued tumor model, both DBN and EBN can efficiently accumulate in tumor sites and feasibly permeate throughout the tumor mass. These biomimetic nanosystems can be preferentially internalized by cancer cells and effectively accessed to CSCs fractions in tumor. The DBN+laser/EBN treatment produces considerable depression of primary tumor growth, drastically eradicates around 80% of CSCs fractions in primary tumor, and results in 95.2% inhibition of lung metastasis. Thus, the biomimetic nanocages can be a promising delivery nanovehicle with preferential CSCs‐accessibility for effective anti‐metastasis 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.

Lymphatic transport of oral drugs allows extraordinary gains in bioavailability and efficacy through avoidance of first-pass hepatic metabolism and preservation of drugs at lymphatic tissues against lymph-mediated diseases. Chylomicrons can transport dietary lipids absorbed from the intestine to the tissues through lymphatic circulation. Herein, we engineered for the first time a chylomicron-pretended mesoporous silica nanocarrier that utilizes the digestion, re-esterification, and lymphatic transport process of dietary triglyceride to promote lymphatic transport of oral drugs. Taking lopinavir (LNV) as a model antiretroviral drug with disadvantages such as poor solubility, high first-pass effect and off-target deposition, this vehicle exhibited several properties belonging to ideal nanocarriers, including high drug load, amorphous dispersion and controlled release in the gastrointestinal tract. Additionally, a nano-bio interaction was demonstrated between nanoparticles and a key protein involved in chylomicron assembly; this biochemical reaction in cellular was utilized for the first time to promote lymphatic transport of nanocarriers for oral delivery. As a result, the chylomicron-pretended nanocarrier afforded 10.6-fold higher oral bioavailability compared with free LNV and effectively delivered LNV to gut-associated lymphoid tissues, where HIV persists and actively evolves. This approach not only promises a potential application to HIV-infected individuals but also opens a new avenue to other lymph-mediated pathologies such as autoimmune diseases and lymphatic tumor metastasis.

We report a simple strategy to prepare Tween 60@2β-CD self-assembly vesicles in aqueous solution as a new drug delivery carrier for cancer chemotherapy. The spherical shape of vesicles was confirmed by transmission electron microscopy (TEM) and mean particle sizes were about 33.7 nm, as measured by dynamic light scattering, micro-IR results indicated that the self-assembly vesicles was driven by hydrogen bonding. Hydrophilic doxorubicin (DOX) was successfully loaded into the self-assembly vesicles with drug loading content of 7.85% and loading efficiency of 42%. In addition, an in vitro cytotoxicity study and cellular uptake assays demonstrated that the DOX-loaded Tween 60@2β-CD vesicles markedly enhanced the cellular uptake and cytotoxicity of DOX toward the Hela cells. Furthermore, when used to evaluate the in vivo therapeutic efficacy in mice bearing the breast cell line (4T1), DOX-loaded vesicles exhibited superior inhibition of tumor growth compared with the DOX solutions.

The lipid bilayer coated mesoporous silica nanocomposites (LMSNs) were synthesized with aim to obtain better performance in the application of drug delivery. Phospholipids composed of soybean lecithin and DSPE-PEG 2000 were pre-prepared into liposomes, then they were allowed to fuse onto the mesoporous silica nanoparticles (MSNs) forming a surrounding lipid bilayer. The obtained LMSNs had an average particle size of 295 nm, zeta potential of −1.0 mV and a good dispersing stability in saline buffers. Facilitated by the affinity of the lipid bilayer with cell membrane, the internalization of LMSNs by cells was markedly increased. In addition, compared with bare MSNs, the cytotoxicity, hemolysis percentage and nonspecific BSA absorption of LMSNs were significantly reduced, making them become more reliable carriers for drug delivery. When encapsulating a model drug, doxorubicin (DOX) into LMSNs, the loading efficiency can reach as high as 16%. The obtained LMSNs-DOX exhibited a pH-responsive release behavior and the presence of the lipid bilayer did not significantly retard the release of DOX. Furthermore, LMSNs greatly enhanced the cellular accumulation and cytotoxicity of DOX toward the MCF-7 cells. In summary, the lipid bilayer coating was a simple and facile strategy to functionalize MSNs, and the obtained LMSNs exhibiting good biocompatibility were promising nanocarriers in improving the cellular uptake and therapeutic efficacy of anticancer drugs.

A family of nanogel drug carriers has been designed to enhance the oral absorption of paclitaxel (PTX). The PAHy-based nanogels were prepared by the interpenetration of poly-α,β-polyasparthydrazide (PAHy) chains and dicarboxyl-poly (ethylene glycol) (CPEG), forming a smart chain network. The PAHy-based nanogels were characterized by Fourier Transform Infrared Spectroscopy (FT-IR), dynamic light scattering (DLS), X-ray diffraction (XRD) and high performance liquid chromatography (HPLC). The adhesion and retention properties of fluorescein isothiocyanate (FITC)-nanogels in vivo were investigated using an in vivo imaging system and confocal laser scanning microscopy (CLSM). The smart nanogels had a particle size of -200 nm, increased the degree and rate of release, and spent over 12 h in the gastrointestinal tract. They also produced excellent adhesion, permeability and retention (APR) effects and increased oral absorption, confirming their use as potential sustained-release carriers for the oral delivery of the hydrophobic anticancer agent PTX.

In this paper, a mesoporous silica nanoparticles (MSN)-based redox and pH dual-responsive delivery system (MSN-SS-PAA) was developed for site-specific drug delivery, in which poly(acrylic acid) (PAA), a polyanion polymer, was grafted on the outlets of MSN via the cleavable disulfide bonds. PAA was chosen as a gatekeeper to block drugs within the mesopores of MSN mainly because PAA possesses many favorable features, such as appropriate molecular weight to block the entrances of MSNs, good biocompatibility, and ability to prolong the blood circulation time and improve the dispersing stability of MSN in physiological conditions. RhB, a fluorescent dye, was used as a model drug. In vitro release profiles indicated that RhB was markedly blocked within the mesopores in the absence of GSH or in pH 7.4 PBS; however, the release of RhB was dramatically increased after the addition of GSH or in pH 5.0 PBS. Moreover, the release of RhB was further improved in the simultaneous presence of GSH and pH 5.0 PBS. This paper provided an exploration of stimuli-responsive delivery system and the results demonstrated that MSN-SS-PAA exhibiting dual-responsive drug release property can be further considered as a promising candidate for cancer therapy.

In this paper, a redox and enzyme dual-stimuli responsive delivery system (MSN-SS-HA) based on mesoporous silica nanoparticles (MSN) for targeted drug delivery has been developed, in which hyaluronic acid (HA) was conjugated on the surface of silica by cleavable disulfide (SS) bonds. HA possesses many attractive features, including acting as a targeting ligand and simultaneously a capping agent to achieve targeted and controlled drug release, prolonging the blood circulation time, and increasing the physiological stability and biocompatibility of MSN. The anticancer drug doxorubicin (DOX) was chosen as a model drug. In vitro drug release profiles showed that the release of DOX was markedly restricted in pH 7.4 and pH 5.0 phosphate buffer solution (PBS), while it was significantly accelerated upon the addition of glutathione (GSH)/hyaluronidases (HAase). In addition, the release was further accelerated in the presence of both GSH and HAase. Confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) showed that MSN-SS-HA exhibited a higher cellular uptake via cluster of differentiation antigen-44 (CD44) receptor-mediated endocytosis compared with thiol (SH)-functionalized MSN (MSN-SH) in CD44 receptor over-expressed in human HCT-116 cells. The DOX-loaded MSN-SS-HA was more cytotoxic against HCT-116 cells than NIH-3T3 (CD44 receptor-negative) cells due to the enhanced cellular uptake of MSN-SS-HA. This paper describes the development of an effective method for using a single substance as multi-functional material for MSN to simultaneously regulate drug release and achieve targeted delivery.

Metastasis is the primary cause resulting in the high mortality of breast cancer. The inherent antimetastasis bioactivity of Pluronic copolymers with a wide range of hydrophilic-lipophilic balance (HLB) including Pluronic L61, P85, P123, F127, F68, and F108 was first explored on metastatic 4T1 breast cancer cells. The results indicated that P85 and P123 could strongly inhibit the migration and invasion of 4T1 cells. The effects of the polymers on cell healing, migration, and invasion exhibited bell-shaped dependencies on HLB of Pluronic copolymers, and the better antimetastasis effects of Pluronic copolymers could be achieved with the HLB between 8 and 16. P85 and P123 themselves could significantly inhibit pulmonary metastasis in 4T1 mammary tumor metastasis model in situ. In addition, a synergetic antimetastasis effect could be achieved during drug combination of doxorubicin hydrochloride (DOX) and P85 or P123 intravenously. The metastasis effects of P85 and P123 both in vitro and in vivo were partially attributed to the downregulation of matrix metalloproteinase-9 (MMP-9). Therefore, Pluronic copolymers with moderate HLB 8-16 such as P85 and P123 could be promising excipients with therapeutics in drug delivery systems to inhibit breast cancer metastasis.

3-D ordered macroporous carbon with different polymer coatings were developed as new oral vaccine immunological systems. Poly dimethyl diallyl ammonium (PDDA), polyethyleneimine (PEI) and chitosan (CTS), three different polymers with electropositive or adsorption-promoting properties, were chosen as the coating materials to endow the vaccine delivery systems with different surface properties. The bovine serum albumin (BSA) was used as a model vaccine. The three different polymer coated systems exhibited similar release rate which minimized the influence of release rate. The measured value of immunoglobulin G (IgG) titers suggested that the sustained release rate of BSA from polymer coated systems exhibited no strengthened effect on the immune response but could delay the appearance of the peak of the IgG titers compared with uncoated system. The electrostatic attraction between the mucosal and positively charged carrier would be useful during the whole immune experiment. In addition, using the coating material with the ability of enhancing mucosal adsorption was important in the mid-late period of immune. The immunoglobulin A (IgA) titers induced by the polymer coated systems were significantly higher than that induced by the oral BSA solution or i.m. BSA with Freund's complete adjuvant (FCA) which suggested the successful mucosal immune response of the three different coated systems. Overall, this work provides valuable information for the development of oral vaccine delivery system.

In this study, paclitaxel (PTX)-loaded polyamidoamin-alkali blue (PTX-P-AB) was prepared in order to investigate the intralymphatic targeting ability and anti-cancer effect after subcutaneous (s.c.) administration. The physicochemical properties and in vitro drug release were evaluated. The lymphatic drainage and lymph nodes (LNs) uptake were examined by pharmacokinetics and distribution recovery of PTX in plasma, LNs, injection site (IS) and tissues after s.c. injection in healthy mice and in tumor-bearing mice. The osmotic pressure of PTX-P-AB affecting the lymphatic targeting was studied. The anti-tumor activity of PTX-P-AB was investigated in mice bearing S180 metastatic tumors. Results showed that PTX-P-AB with suitable and stable physicochemical properties could be used for in vivo lymphatic studies, and displayed the more rapid lymphatic absorption, the higher AUC value in LNs, the longer LNs residence time and the higher metastasis-inhibiting rate compared with Taxol®. Enhanced lymphatic drainage from the IS and uptake into lymph by increasing the osmotic pressure of PTX-P-AB indicated that PTX-P-AB possesses the double function of lymphatic tracing and lymphatic targeting, and suggested the potential for the development of lymphatic targeting vectors and the lymphatic tracer for treatment and diagnosis.

We reported a magnetic targeted drug delivery system based on core/shell structural magnetic mesoporous silica nanoparticles (MMSNs) and the surface of MMSNs was coated by gelatin layer. In this system, the gelatin layer retarded the diffusion of paclitaxel (PTX, model drug) from quickly moving into the bulk solution to achieve sustained release of PTX. In addition, glutaraldehyde (GA) was used as crosslinking agent to crosslink the coating layer and the release of PTX could be regulated by adjusting the degree of crosslinking of the gelatin layer. The gelatin coated MMSNs (MMSN@GELs) had a saturated magnetization of 5.53 emu/g and could facilely response to an external magnet. To confirm our hypothesis that the carriers could be guided by an external magnetic field in vivo, the ex vivo imaging study and quantitative analysis were conducted. The results reflected that the external magnet altered the biodistribution of the magnetic carriers, so that more magnetic carriers were found to accumulate in tumors rather than to accumulate in normal tissues. Moreover, tumor reduction study reflected that the tumor growth of the group treated with PTX/MMSN@GELs in the presence of an external magnetic field were significantly delayed without an obvious body weight loss compared with PTX/MMSN@GELs in the absence of the magnet and with the commercial Taxol® at the same dose. All the results suggested that MMSNs coated by gelatin would be promising drug carriers for effective delivery of chemotherapeutic agents.

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.