Azobenzene-based liposomes with nanomechanical action for cytosolic chemotherapeutic drug delivery.

The stimuli-responsive nano-carriers are at the forefront of research in nanotechnology and materials science. These advanced systems are designed to alter their physicochemical properties upon exposure to specific stimuli, enabling controllable and targeted delivery of therapeutic agents. Nevertheless, limited endosomal escape reduces the drug bioavailability in clinical use. We herein report azobenzene (Azo)-based liposomes, prepared by co-assembling the photoisomerizable cationic Azo lipids and helper lipids, which achieve controllable doxorubicin (Dox) release and enhanced cytosolic transport upon light irradiation. Azo lipids undergo reversible isomerization between cis-isomers and trans-isomer when received UV and visible (Vis) light irradiation, causing liposomal membrane permeability changes for controlled drug release. Moreover, the nanomechanical action created by the isomerization of Azo lipids promotes the endosomal escape of the liposomes. DSPC-Azo liposomes, with minimal Dox leakage, showed significant tumor cell killing upon irradiation. For in vivo study, we co-encapsulated the upconverting nanoparticles (UCNPs), which can convert the near-infrared (NIR) light into UV/Vis emissions, facilitating Azo units activation. UCNP/Dox-loaded DSPC-Azo liposomes inhibited tumor growth under NIR irradiation in a 4T1 tumor-bearing mouse model.

Photo-controllable drug releasing bulk polyacrylic intraocular lens material for safer posterior capsular opacification prevention.

Posterior capsular opacification (PCO) is the most common complication that occurs after intraocular lens (IOL) implantation in cataract therapy. In recent years, IOLs have been developed as drug delivery platforms, but concerns over the safety of uncontrolled proliferative drug release have arisen. Therefore, a controlled drug release strategy is needed for safer PCO prevention. In this study, a new monomer contained coumarin group was introduced in material preparation, and poly(ethylene glycol phenyl ether methacrylate-co-2-(2-ethoxyethoxy) ethyl acrylate-co-7-(2-methacryloyloxyethoxy)-4-methylcoumarin) (PEEC) acrylic IOL materials were synthesized. The antiproliferative drug 5-fluorouracil (5-FU) could be chemically grafted to the PEEC IOL materials easily via a light induced [2 + 2] cycloaddition reaction with the coumarin group, getting drug-loaded IOL (PEEC@5-FU IOL). The PEEC@5-FU IOL exhibited excellent optical and mechanical properties and biocompatibility. More importantly, the loaded 5-FU could be easily controlled from release by light irradiation via photo-dissociation of the cyclobutane ring that was obtained by the [2 + 2] cycloaddition reaction of 5-FU and coumarin. The in vitro and in vivo experiments demonstrated that such photo-controllable drug release IOL could effectively prevent PCO after implantation in a safe way.

Self-controllable proteinic antibacterial coating with bacteria-triggered antibiotic release for prevention of periprosthetic infection.

Periprosthetic infection is a devastating postimplantation complication in which a biofilm layer harboring invasive microorganisms forms around orthopedic implants, leading to severe implant failure and patient morbidity. Despite the development of several infection-triggered antibiotic release approaches, most current antibacterial coatings are susceptible to undesired antibiotic leakage or mechanical disintegration during prosthesis installation. Herein, we propose a self-controllable proteinic antibacterial coating capable of both long-lasting adherence onto titanium implant substrates over the implant fixation period and instantaneous bacterial eradication. Importantly, the pH-dependent reversible metal coordination of mussel adhesive protein (MAP) enabled bacterial concentration-dependent antibiotic delivery in response to infection-induced acidification. In addition, the MAP coating exhibited superior self-healable adhesive properties and scratch resistance, which enabled to avert issues associated with mechanical damages, including peeling and cracking, often occurring in conventional implant coating systems. The gentamicin-loaded MAP coating exhibited complete inhibition of bacterial growth in vivo against Staphylococcus aureus penetrations during implantation surgery (immediate infection) and even 4 weeks after implantation (delayed infection). Thus, our antibiotic-loaded MAP hydrogel coating can open new avenues for self-defensive antibiotic prophylaxis to achieve instant and sustainable bacteriocidal activity in orthopedic prostheses. © 2017 Elsevier Inc. All rights reserved.

Mussel-inspired controllable drug release hydrogel for transdermal drug delivery: Hydrogen bond and ion-dipole interactions.

Hydrogels have broad application prospects in drug delivery due to their biocompatibility, high water content and three-dimensional structure. However, the regulation of drug release from hydrogels is an important issue in medical applications. At the same time, water also has an important impact on drug release. In this study, a hydrogel with hydrogen bond and ion dipole interaction (PAHDP) was prepared by introducing catechol group into polymer to regulate drug release. Ten model drugs were selected to explore the relationship and mechanism of action among polymer, drug and water. The results showed that PAHDP had excellent adhesion and safety. Drug release test showed that 10 kinds of drugs had different drug release trends, and the release amount was negatively correlated with drug polarizability and LogP. In addition, in vitro transdermal test and pharmacokinetic results showed that the hydrogel based on PAHDP achieved increased or decreased blood drug concentration, and the area under the concentration-time curve (AUC) of >1.5 times showed its potential to regulate drug release. The mechanism study showed that the hydrogen bond and ion dipole interaction between polymer and drug were affected by drug polarizability and LogP, and the distribution of water in different states was changed. Hydrogen bond and ion dipole interactions synergistically control drug release. Therefore, the mussel inspired PAHDP hydrogel has the potential to become a controllable drug delivery system.

NIR-triggered thermosensitive polymer brush coating modified intraocular lens for smart prevention of posterior capsular opacification.

Posterior capsule opacification (PCO) is the most common complication after cataract surgery. Drug-eluting intraocular lens (IOLs) is a promising concept of PCO treatment in modern cataract surgery. However, the large dose of drugs in IOL leads to uncontrollable and unpredictable drug release, which inevitably brings risks of overtreatment and ocular toxicity. Herein, a low-power NIR-triggered thermosensitive IOL named IDG@P(NIPAM-co-AA)-IOL is proposed to improve security and prevent PCO by synergetic controlled drug therapy and simultaneous photo-therapy. Thermosensitive polymer brushes Poly(N-isopropylacrylamide-co-Acrylic acid) (P(NIPAM-co-AA)) is prepared on IOL via surface-initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization. Then, Doxorubicin (DOX) and Indocyanine green (ICG) co-loaded Gelatin NPs (IDG NPs) are loaded in P(NIPAM-co-AA) by temperature control. The IDG NPs perform in suit photodynamic & photothermal therapy (PTT&PDT), and the produced heat also provides a trigger for controllable drug therapy with a cascade effect. Such functional IOL shows excellent synergistic drug-phototherapy effect and NIR-triggered drug release behavior. And there is no obvious PCO occurrence in IDG@P(NIPAM-co-AA) IOL under NIR irradiation compared with control group. This proposed IDG@P(NIPAM-co-AA)-IOL serves as a promising platform that combines phototherapy and drug-therapy to enhance the therapeutic potential and medication safety for future clinical application of PCO treatment.

Coumarin-Based Fluorescent Inhibitors for Photocontrollable Bioactivation.

Activation of the IRE-1/XBP-1 pathway is related to many human diseases. Coumarin-based derivatives acting as both IRE-1 inhibitors and bright fluorophores are highly desirable to establish an integrated fluorescent inhibitor system. Here, we take insights into the aqueous stability of a photocaged IRE-1 inhibitor PC-D-F07 through a structure activity relationship. The substituent effects indicate that the electron-withdrawing -NO2 moiety in the photocage combined with the tricyclic coumarin fluorophore contribute to the structural stability of PC-D-F07. To optimize the photocage of PC-D-F07, we incorporate a 1-ethyl-2-nitrobenzyl or 2-nitrobenzyl photolabile moiety on the hydroxyl group of the IRE-1 inhibitor to generate RF-7 and RF-8. Upon photoactivation, both RF-7 and RF-8 present an increased fluorescence response, sequentially enabling the unlocking of the ortho-1,3-dioxane acetal for the release of active IRE-1 inhibitors. Moreover, RF-7 exhibits a high repolarization ratio of converting M2-type tumor-associated macrophages (M2-TAMs) to M1-type immune-responsive macrophages. This provides a novel prodrug strategy of modulating druggable fluorophore backbones to achieve spatiotemporally controllable drug release for precise cancer treatment.

Physically and Chemically Crosslinked, Tannic Acid Embedded Linear PEI-Based Hydrogels and Cryogels with Natural Antibacterial and Antioxidant Properties.

Linear polyethyleneimine (L-PEI) was obtained from the acidic hydrolysis of poly(2-ethyl-2-oxazoline) and employed in the synthesis of physically crosslinked L-PEI hydrogel, PC-L-PEIH, chemically crosslinked L-PEI hydrogel, CC-L-PEIH, and cryogels, CC-L-PEIC. The preparation of L-PEI-based hydrogel networks was carried out in two ways: 1) by cooling the L-PEI solution from 90 °C to room temperature, and 2) by crosslinking L-PEI chains with a crosslinker, glycerol diglycidyl ether = 20 °C for CC-L-PEIC. Furthermore, a polyphenolic compound, tannic acid (TA), with superior antibacterial, antioxidant, and anti-inflammatory properties as an active biomedical functional agent, was encapsulated during the synthesis process within L-PEI-based hydrogels and cryogels, at 10% and 25% (w/w) based on the L-PEI amount. A linear and higher TA release was observed from physically crosslinked PEI-based hydrogels containing 10% and 25% TA-containing PC-L-PEI/TAH within 6 h, with 9.5 ± 05 mg/g and 60.2 ± 3.8 mg/g cumulative released amounts, respectively. A higher antioxidant activity was observed for 25% TA containing PC-L-PEI/TAH with 53.6 ± 5.3 µg/mL total phenol content and 0.48 ± 0.01 µmole Trolox equivalent/g. The minimum bactericidal concentration (MBC) of PC-L-PEIH and CC-L-PEIC networks against both E. coli (ATCC 8739) and Gram-positive B. subtilis (ATCC 6633) bacteria was determined at 5 mg/mL, whereas the MBC value of 10 mg/mL for CC-L-PEIH networks against the same bacteria was achieved.

Blood-brain Barrier Permeable and Multi-stimuli Responsive Nanoplatform for Orthotopic Glioma Inhibition by Synergistic Enhanced Chemo-/Chemodynamic/Photothermal/Starvation Therapy.

Glioblastoma (GBM) is a common malignant tumor in brain, and the treatment is still a challenge owing to the high invasiveness and the existence of blood-brain barrier (BBB). Although temozolomide (TMZ) is the first line medication, its efficacy is not ideal, which is related to the defect of dose distribution and drug resistance. It is urgent to develop a novel BBB-permeable nanoagent with multiple therapeutic modalities for improving the treatment effect of GBM. In this work, we constructed an intelligent BBB-permeable nanoplatform (CTHG-Lf NPs) with hollow mesoporous copper sulfide nanoparticles (HM-CuS NPs) as temozolomide (TMZ) carrier and hyaluronic acid (HA) as gatekeeper, as well as further modification with glucose oxidase (GOx) and lactoferrin (Lf) for highly efficient synergistic therapy of orthotopic GBM. The modification of Lf endows CTHG-Lf NPs with good target and BBB-permeable ability. HA not only prevents the TMZ leakage during circulation, but also achieves responsive drug release at tumor site for effective chemotherapy (CT). GOx provides high hydrogen peroxide (H2O2) and gluconic acid for improving the treatment effect of chemodynamic therapy (CDT), and realizes the starvation therapy (ST) by consuming glucose. The good photothermal effect of CTHG-Lf NPs achieves the "mild" photothermal therapy (PTT), while enhancing the efficiency of Fenton-like reaction. The synergistic strategy with CT/CDT/PTT/ST can not only promote brain drug delivery, but also realize the combination of multiple mechanisms for effective tumor growth suppression in vivo.

Application of nanotechnology in local anesthetic drug sustained release and light-responsive controlled release / 药学学报

Local anesthetic drugs are commonly used to block the conduction function of patient's nerves temporarily for anesthesia during surgery or to provide targeted analgesia after trauma. Compared with general anesthetics, local anesthetics makes less impact on the physiological status and alleviates pain complications in the presence of clear consciousness. However, its clinical application is still limited by its systemic toxicity, as well as toxicity to nerves and muscles, duration of action and lack of penetration. Nanotechnology can help it penetrate the physiological barrier, prolong the time of nerve block, and reduce toxic side effects. In addition, by building a light-responsive release system, local anesthetics can be released on demand, enhancing drug effectiveness and safety. However, in addition to the problems of poor consistency and high production costs, the system of light response release is still limited in application due to the limitation of the depth of penetration of the tissue. According to the current research progress, this paper briefly introduces and analyzes the main dosage forms, hoping to provide new ideas for the responsive release of local anesthetic drugs.

Smart-Temporary-Film-Based Local-Delivery System with Controllable Drug-Release Behavior.

The development of a simple local drug-delivery system that exhibits the advantages of macro- and microscale carriers with controllable drug-release behavior is still highly desired. Herein, in this work, a smart temporary film was prepared from doxorubicin (DOX)-loaded shape-memory microgels via a simple hot-compression programming method. The temporary film showed a very smooth surface and easy handing, as well as macroscopy mechanical properties, which could disintegrate into the microgels with heating at 45 °C. In this case, the temporary film showed a controllable DOX release behavior when compared with the microgels, which could release the DOX on demand. Consequently, the temporary film exhibited weaker cytotoxicity to normal cells and a much longer antitumor capability, as well as a higher drug-utilization efficiency when compared with microgels. Therefore, the smart temporary film has high potential as a candidate for use as a local drug-delivery system.

Orthogonal Design of Supramolecular Prodrug Vesicles via Water-Soluble Pillar[5]arene and Betulinic Acid Derivative for Dual Chemotherapy.

Supramolecular prodrug vesicles with efficient property for dual chemotherapy have been successfully constructed based on the orthogonal self-assembly between a water-soluble pillar[5]arene host (WP5) and a betulinic acid guest (BA-D) as well as doxorubicin (DOX). Under the acidic microenvironment of cancer cells, both the encapsulated anticancer drug DOX and prodrug BA-D can be effectively released from DOX-loaded WP5⊃BA-D prodrug vesicles for combinational chemotherapy. Furthermore, bioexperiments indicate that DOX-loaded prodrug vesicles can obviously enhance the anticancer efficiency based on the cooperative effect of DOX and BA-D, while remarkably reducing the systematic toxicity in tumor-mice, displaying great potential applications in combinational chemotherapy for cancer treatments.

Drug Release from Gelsolin-Targeted Phase-Transition Nanoparticles Triggered by Low-Intensity Focused Ultrasound.

PURPOSE: Current strategies for tumour-induced sentinel lymph node detection and metastasis therapy have limitations. It is essential to identify and provide warnings earlier for tumour metastasis to carry out effective clinical interventions. In addition, traditional cancer chemotherapy encounters drastic limitations due to the nonspecific delivery of antitumour drugs and severe side effects. We aimed to exploit the potential of gelsolin (GSN) monoclonal antibody as a targeting agent and perfluorohexane (PFH) as a phase-transition agent to maximize the cytotoxic effect of poly(lactic-co-glycolic acid) (PLGA) nanoparticle-based drug controllable release systems for Hca-F cells. METHODS: We co-encapsulated PFH and doxorubicin (DOX) into PLGA nanoparticles (NPs) and further conjugated GSN monoclonal antibody onto the surface of NPs to form GSN-targeted phase transition polymer NPs (GSN-PLGA-PFH-DOX) for both imaging and therapy of tumours and metastatic lymph nodes. To promote and trigger drug release on demand, low-intensity focused ultrasound (LIFU) was applied to achieve a controllable release of the encapsulated drug. RESULTS: GSN-PLGA-PFH-DOX NPs exhibited characteristics such as a narrow size distribution and smooth surface. GSN-PLGA-PFH-DOX NPs could also specifically bind to Hca-F cells and increase the ultrasound contrast agent (UCA) image contrast intensity. GSN-PLGA-PFH-DOX NPs enable GSN-mediated targeting and biotherapeutic effects as well as LIFU-responsive drug release, resulting in synergistic cytotoxic effects in GSN-overexpressing cells in vitro. CONCLUSION: Our work might provide a strategy for the imaging and chemotherapy of primary tumours and their metastases.

Reduction-Triggered Paclitaxel Release Nano-Hybrid System Based on Core-Crosslinked Polymer Dots with a pH-Responsive Shell-Cleavable Colorimetric Biosensor.

Herein, we describe the fabrication and characterization of carbonized disulfide core-crosslinked polymer dots with pH-cleavable colorimetric nanosensors, based on diol dye-conjugated fluorescent polymer dots (L-PD), for reduction-triggered paclitaxel (PTX) release during fluorescence imaging-guided chemotherapy of tumors. L-PD were loaded with PTX (PTX loaded L-PD), via π-π stackings or hydrophobic interactions, for selective theragnosis by enhanced release of PTX after the cleavage of disulfide bonds by high concentration of glutathione (GSH) in a tumor. The nano-hybrid system showed fluorescence quenching behavior with less than 2% of PTX released under physiological conditions. However, in a tumor microenvironment, the fluorescence recovered at an acidic-pH, and PTX (approximately 100% of the drug release) was released efficiently out of the matrix by reduction caused by the GSH level in the tumor cells, which improved the effectiveness of the cancer treatment. Therefore, the colorimetric nanosensor showed promising potential in distinguishing between normal and cancerous tissues depending on the surrounding pH and GSH concentrations so that PTX can be selectively delivered into cancer cells for improved cancer diagnosis and chemotherapy.

Modification of fliposomes with a polycation can enhance the control of pH-induced release.

PURPOSE: Nowadays, the development of stimuli-sensitive nanocontainers for targeted drug delivery is of great value. Encapsulation of a drug in a pH-sensitive liposomal container not only provides protective and transport functions, but also helps to create a system with a controlled release mechanism. METHODS: In this study, we investigated the influence of a cationic polypeptide on the pH-induced release of anticancer drug doxorubicin (DXR) from the anionic fliposomes - liposomes consisting of a neutral lipid, an anionic lipid (prone to interact with a polycation), and a lipid trigger (imparting the pH-sensitivity). RESULTS: First, we showed the possibility to control the pH-induced release by the simple modification of the anionic fliposomes with linear polylysine. Second, we optimized the fliposomal composition such that the obtained fliposomes responded to the pH changes only when complexed with the polycation ("turning on" the release). Finally, pH-induced release from the polylysine-modified anionic fliposomes was tested on an anticancer drug DXR. CONCLUSION: We have succeeded in developing "smart" stimuli-sensitive nanocontainers capable of tunable controlled release of a drug. Moreover, based on the data on release of a low molecular salt, one can predict the release profile of DXR.

Artificially controlled degradable nanoparticles for contrast switch MRI and programmed cancer therapy.

BACKGROUND: Utilizing the permeability enhancement and irreversible biomolecule denaturation caused by hyperthermia, photothermal-chemo synergistic therapy has shown great potential in clinical cancer treatment. PURPOSE: The objective of this study was to provide a novel controlled drug release method to improve the efficiency of photothermal-chemo synergistic therapy. PATIENTS AND METHODS: HCT116 tumor-bearing mice were selected as modal for the study of cancer theranostics efficiency. The T2 to T1 magnetic resonance imaging contrast switch was studied in vivo. Analyses of the tumor growth of mice were carried out to evaluate the tumor therapy efficiency. RESULTS: We developed novel artificially controlled degradable Co3O4 nanoparticles and explored their potential in drug delivery/release. In the presence of ascorbic acid (AA), the designed nanomaterials can be degraded via a redox process and hence release the loaded drugs. Importantly, the AA, in the lack of l-gulonolactone oxidase, cannot be synthesized in the body of typical mammal including human, which suggested that the degradation process can be controlled artificially. Moreover, the obtained nanoparticles have outstanding photothermal conversion efficiency and their degradation can also result in an magnetic resonance imaging contrast enhancement switch from T2 to T1, which benefits the cancer theranostics. CONCLUSION: Our results illustrated that the artificially controlled degradable nanoparticles can serve as an alternative candidate for controllable drug release as well as a platform for highly efficient photothermal-chemo synergistic cancer theranostics.

BSA-based Cu2Se nanoparticles with multistimuli-responsive drug vehicles for synergistic chemo-photothermal therapy.

Functionalized-nanoparticles have been developed as novel therapeutic delivery platform for simultaneous drug loading and therapy over the past decade. Rationally-designed biocompatible nanosystem simultaneously with multistimuli-responsive property and synergistic therapeutic potential are highly desirable for modern biological applications. Herein, Cu2Se nanoparticles (Cu2SeNPs) with suitable size have been functionalized by bull serum albumin (BSA) through a simply, facile and controllable method. As a result, Cu2SeNPs modified by BSA (BSA-Cu2SeNPs) showed excellent biocompatibility and stability. The strong absorbance of BSA-Cu2SeNPs at near infrared region imparts them with high photothermal efficiency. Then loading doxorubicin (DOX, anticancer drug) on the surface of BSA-Cu2SeNPs, and consequently, a novel multifunctional nanosystem of BSA-Cu2SeNPs-DOX is designed. The BSA-Cu2SeNPs can achieve high DOX loading capacity (approximately 157 µg DOX per mg of Cu2Se). Furthermore, a rational and precise release of DOX from the BSA-Cu2SeNPs-DOX could be easily realized under the stimulates of the pH and temperature, which remarkably improved antitumor efficacy of combined chemotherapy and photothermal therapy triggered by 808 nm NIR laser. Thus, the BSA-Cu2SeNPs-DOX could serve as an ideal nanoplatform for cancer diagnosis and treatment in future. The results of cell experiments show that the BSA-Cu2SeNPs-DOX exhibited favorable selective cellular uptake cells. Under the NIR laser irradiation, BSA-Cu2SeNPs-DOX could induce the excessive expression of ROS, eventually leading to the death of U251 cells. Both in vitro and in vivo experiments indicate that the nanosystem of BSA-Cu2SeNPs-DOX showed excellent synergistic therapeutic effect and multistimuli-responsive drug vehicle, which will exert huge potential for future clinical application.

Magnesium-Engineered Silica Framework for pH-Accelerated Biodegradation and DNAzyme-Triggered Chemotherapy.

Inorganic nanocarriers have shown their high performance in disease theranostics in preclinical animal models and further great prospects for clinical translation. However, their dissatisfactory biodegradability and pre-drug leakage with nonspecificity to lesion sites significantly hinders the possible clinical translation. To solve these two critical issues, a framework-engineering strategy is introduced to simultaneously achieve enhanced biodegradability and controllable drug releasing, based on the mostly explored mesoporous silica-based nanosystems. The framework of mesoporous silica is engineered by direct Mg doping via a generic dissolution and regrowth approach, and it can transform into the easy biodegradation of magnesium silicate nanocarriers with simultaneous on-demand drug release. Such magnesium silicate nanocarriers can respond to the mild acidic environment of tumor tissue, causing the fast breaking up and biodegradation of the silica framework. More interesting, the released Mg2+ can further activate Mg2+ -dependent DNAzyme on the surface of hollow mesoporous magnesium silicate nanoparticles (HMMSNs) to cleave the RNA-based gatekeeper, which further accelerates the release of loaded anticancer drugs. Therefore, enhanced anticancer efficiency of chemotherapeutic drugs assisted by the biodegradable intelligent HMMSNs is achieved. The high biocompatibility of nanocarriers and biodegradation products is demonstrated and can be easily excreted via feces and urine guaranteeing their further clinical translation.

Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy.

Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and DPPA-1, was synthesized and coassembled with NLG919. The nanostructure swelled when it encountered the weakly acidic tumor niche where DEAP molecules were protonated, and further collapsed due to the cleavage of the peptide substrate by MMP-2 that is highly expressed in tumor stroma. The localized release of DPPA-1 and NLG919 created an environment which favored the survival and activation of cytotoxic T lymphocytes, leading to the slowdown of melanoma growth and increase of overall survival. Together, this study offers new opportunities for dual-targeted cancer immunotherapy through functional peptide assembling nanoparticles with design features that are sequentially responsive to the multiple hallmarks of the tumor microenvironment.

pH-responsive drug release and real-time fluorescence detection of porous silica nanoparticles.

In this work, pH-sensitive "dual-switch" porous silica (pSiO2) nanoparticles (NPs) were constructed for drug delivery. Poly(acrylic acid) (PAA) was grafting onto the internal and external surfaces of amino groups functionalized porous silica (pSiO2-NH2) NPs by the amidation between the amino groups and the carboxyl groups of PAA for pH triggered drug release. The resultant pSiO2/PAA NPs have an average diameter of 50-60nm and high specific surface area (914m2·g-1). To improve the loading capacity, ZnO quantum dots (QDs) were used to block the partial pores of pSiO2/PAA and the loading capacity reached to 28% for methotrexate (MTX) model drug. The in vitro cellular cytotoxicity test and a hemolysis assay demonstrated that the pSiO2/PAA/ZnO NPs were highly biocompatible and suitable to utilize as drug carriers. The MTX-loaded pSiO2/PAA/ZnO NPs displayed more efficient cytotoxic to HepG2 cells than free MTX. The pSiO2/PAA/ZnO NPs displayed low premature, pH-responsive release and pH-dependent fluorescence. Moreover, pH-dependent fluorescence enables to trace MTX release behavior.

Synthesis and characterization of dendritic star-shaped zwitterionic polymers as novel anticancer drug delivery carriers.

In this work, a novel dendritic star-shaped zwitterionic polymer, polyamidoamine-graft-poly[3-dimethyl (methacryloyloxyethyl) ammonium propanesulfonate] (PAMAM-g-PDMAPS), was synthesized. PAMAM dendrimers (generation 2, G2) were firstly prepared and then converted into the PAMAM-Br macroinitiator with 2-bromoisobutyryl bromide for ATRP. Finally, ATRP of zwitterionic DMAPS was carried out to obtain the dendritic star-shaped polymers PAMAM-g-PDMAPS with different PDMAPS chain lengths. Fourier transform-infrared spectroscopy, (1)H NMR, dynamic laser light scattering (DLS), and TEM were used to characterize the polymers. Encapsulation of adriamycin (ADR) by PAMAM-g-PDMAPS nanoparticles and ADR release behavior from ADR-loaded PAMAM-g-PDMAPS nanoparticles were investigated in detail. PAMAM-g-PDMAPS polymers, even starting from low-generation PAMAM core (G2), were found to show high loading efficiency for ADR because ADR existed not only within G2 PAMAM cores but also in PDMAPS layers. The release profile of ADR from ADR-loaded PAMAM-g-PDMAPS nanoparticles was pH-sensitive and could be controlled by the length of PDMAPS chains. Cell viability studies indicated that ADR-loaded PAMAM-g-PDMAPS could effectively restrain the growth of HepG2 cells and even kill them, whereas PAMAM-g-PDMAPS exhibited nontoxicity. All these results demonstrated that dendritic star-shaped zwitterionic polymers PAMAM-g-PDMAPS are attractive candidates as anticancer drug delivery carriers.