High Drug Payload Research Articles

Tumor-Specific Endogenous FeII-Activated, MRI-Guided Self-Targeting Gadolinium-Coordinated Theranostic Nanoplatforms for Amplification of ROS and Enhanced Chemodynamic Chemotherapy.

Low drug payload and lack of tumor-targeting for chemodynamic therapy (CDT) result in an insufficient reactive oxygen species (ROS) generation, which seriously hinders its further clinical application. Therefore, how to improve the drug payload and tumor targeting for amplification of ROS and combine it with chemotherapy has been a huge challenge in CDT. Herein, methotrexate (MTX), gadolinium (Gd), and artesunate (ASA) were used as theranostic building blocks to be coordinately assembled into tumor-specific endogenous FeII-activated and magnetic resonance imaging (MRI)-guided self-targeting carrier-free nanoplatforms (NPs) for amplification of ROS and enhanced chemodynamic chemotherapy. The obtained ASA-MTX-GdIII NPs exhibited extremely high drug payload (∼96 wt %), excellent physiological stability, long circulating ability (half-time: ∼12 h), and outstanding tumor accumulation. Moreover, ASA-MTX-GdIII NPs could be specifically uptaken by tumor cells via folate (FA) receptors and subsequently be disassembled via lysosomal acidity-induced coordination breakage, resulting in drug burst release. Most strikingly, the produced ASA could be catalyzed by tumor-specific overexpressed endogenous FeII ions to generate sufficient ROS for enhancing the main chemodynamic efficacy, which could exert a synergistic effect with the assistant chemotherapy of MTX. Interestingly, ASA-MTX-GdIII NPs caused a lower ROS generation and toxicity on normal cell lines that seldom expressed endogenous FeII ions. Under MRI guidance with assistance of self-targeting, significantly superior synergistic tumor therapy was performed on FA receptor-overexpressed tumor-bearing mice with a higher ROS generation and an almost complete elimination of tumor. This work highlights ASA-MTX-GdIII NPs as an efficient chemodynamic-chemotherapeutic agent for MRI imaging and tumor theranostics.

Doxorubicin Encapsulated in TPGS-Modified 2D-Nanodisks Overcomes Multidrug Resistance.

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.

Nanofibrous silica microparticles/polymer hybrid aerogels for sustained delivery of poorly water-soluble camptothecin

The surface functionalization of nanoporous silica materials with chemical agents opens up numerous possibilities, including improvement in the materials’ ability to carry high payloads of drugs. In this study, KCC-1 nanofibrous silica microparticles are functionalized with methyl groups and then combined with poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) to produce hybrid aerogels that can deliver a poorly water-soluble anticancer drug. The synthetic steps involve freeze-drying a polymer solution of PVA and PAA that contains methyl-modified KCC-1 microparticles and then cross-linking the two polymers via a solid-state reaction. Benefiting from the incorporated methyl-modified KCC-1 microparticles, the hybrid aerogels can load and deliver a payload of camptothecin (CPT), an anticancer drug with antitumor activity but limited clinical application due to its hydrophobicity. The aerogels also show a sustained release of CPT for more than two weeks. The drug release profile can further be tuned by varying the relative amounts of PVA, PAA, and methyl-modified KCC-1. The aerogels are biocompatible to healthy cells, such as immortalized human epithelial (HaCaT), African green monkey kidney (Vero) and murine fibroblast (L929) cells. When loaded with CPT, they show potent antitumor activity against HeLa (HPV18-positive), SiHa (HPV16-positive) and C33A (HPV-negative) cancer cells, significantly inhibiting cell growth.

DNA Nanostructure as an Efficient Drug Delivery Platform for Immunotherapy.

Immunotherapy has received increasing attention due to its low potential side effects and high specificity. For instance, cancer immunotherapy has achieved great success. CpG is a well-known and commonly used immunotherapeutic and vaccine adjuvant, but it has the disadvantage of being unstable and low in efficacy and needs to be transported through an effective nanocarrier. With perfect structural programmability, permeability, and biocompatibility, DNA nanostructures are one of the most promising candidates to deliver immune components to realize immunotherapy. However, the instability and low capability of the payload of ordinary DNA assemblies limit the relevant applications. Consequently, DNA nanostructure with a firm structure, high drug payloads is highly desirable. In the paper, the latest progress of biostable, high-payload DNA nanoassemblies of various structures, including cage-like DNA nanostructure, DNA particles, DNA polypods, and DNA hydrogel, are reviewed. Cage-like DNA structures hold drug molecules firmly inside the structure and leave a large space within the cavity. These DNA nanostructures use their unique structure to carry abundant CpG, and their biocompatibility and size advantages to enter immune cells to achieve immunotherapy for various diseases. Part of the DNA nanostructures can also achieve more effective treatment in conjunction with other functional components such as aPD1, RNA, TLR ligands.

Effective delivery of mycophenolic acid by oxygen nanobubbles for modulating immunosuppression.

Immunosuppressive drugs are crucial for preventing acute graft rejection or autoimmune diseases. They are generally small molecules that require suitable drug carriers for ensuring stability, bioavailability, and longer half-life. Mycophenolic acid (MPA) is an extensively studied immunosuppressive drug. However, it requires suitable carriers for overcoming clinical limitations. Currently, lipid-shelled micro- and nanobubbles are being thoroughly investigated for diagnostic and therapeutic applications, as they possess essential properties, such as injectability, smaller size, gaseous core, high surface area, higher drug payload, and enhanced cellular penetration. Phospholipids are biocompatible and biodegradable molecules, and can be functionalized according to specific requirements.Methods: In this study, we synthesized oxygen nanobubbles (ONBs) and loaded the hydrophobic MPA within the ONBs to generate ONB/MPA. Peripheral blood mononuclear cells (PBMCs) were treated with ONB/MPA to determine the suppression of immune response by measuring cytokine release. In vivo murine experiments were performed to evaluate the effectiveness of ONB/MPA in the presence of inflammatory stimulants.Results: Our results suggest that ONBs successfully delivered MPA and reduced the release of cytokines, thereby controlling inflammation and significantly increasing the survival rate of animals.Conclusion: This method can be potentially used for implantation and for treating autoimmune diseases, wherein immunosuppression is desired.

Multifunctional Mesoporous Polydopamine With Hydrophobic Paclitaxel For Photoacoustic Imaging-Guided Chemo-Photothermal Synergistic Therapy.

BackgroundChemo-photothermal therapy has attracted intensive attention because of its low side effects and better therapeutic efficiency. Although many photothermal agents have been loaded with chemotherapeutic drugs for chemo-photothermal therapy, their applications are limited by complex synthetic protocols and long-term safety. Therefore, there is significant clinical value in the development of a simple system of biocompatible and biodegradable photothermal nanomaterials with high payloads of chemotherapeutic drugs for chemo-photothermal synergistic therapy.Materials and methodsIn this study, PEG-modified polydopamine nanoparticles with mesoporous structure (MPDA-PEG) were successfully obtained by an emulsion-induced interface assembly strategy. Subsequently, paclitaxel (PTX) dissolved in acetone was loaded into the mesoporous channels of MPDA-PEG nanoparticles by solution absorption method. A PTX-loaded MPDA-PEG (MPDA-PEG-PTX) nanoplatform for combination of photothermal therapy (PTT) and chemotherapy was developed.ResultsThe synthesized MPDA-PEG nanoparticles had a great photothermal effect under near-infrared (NIR) laser irradiation and exhibited an enhanced photothermal effect with the increase of particle size. Meanwhile, MPDA-PEG nanoparticles also had a high payload of PTX, and the PTX release could be greatly accelerated by elevated temperature from photothermal effect. In MTT cytotoxicity assay, A549 cells incubated with MPDA-PEG-PTX under NIR laser irradiation (PTT + chemotherapy group) exhibited better therapeutic effect than single chemotherapy (MPDA-PEG-PTX group) and PTT (MPDA-PEG + Laser group). The synergistic therapeutic effect of MPDA-PEG-PTX with NIR laser irradiation in vivo was further investigated under the guidance of photoacoustic imaging (PAI), tumors of nude mice treated with MPDA-PEG-PTX with NIR laser irradiation were completely eliminated with minimal side effect.ConclusionThe MPDA-PEG-PTX nanoplatform is a simple and effective platform which can completely inhibit tumor growth with minimal side effects under NIR irradiation, and it exhibits better therapeutic effect than single chemotherapy and PTT.

Pyrazinoic acid-Poly(malic acid) biodegradable nanoconjugate for efficient intracellular delivery

Tuberculosis is an infectious disease affecting mostly lungs, that is still considered a health global problem as it causes millions of deaths worldwide. Current treatment is effective but associated with severe adverse effects due to the high doses of each anti-tuberculosis drug daily administrated by oral therapy. For the first time, a pyrazinoic acid (PA) biodegradable nanoconjugate was synthesized and developed for pulmonary administration in an attempt to reduce the administered doses by achieving a high drug payload and controlled release at the target site. The conjugate was synthesized by coupling pyrazinoic acid on carboxylic groups of poly(malic acid), which is a biodegradable and biocompatible polymer, and posteriorly self-assembled into nanoconjugates. Characterization confirmed the formation of nanometric, spherical and negatively charged pyrazinoic acid nanoconjugate (NC-PA). NC-PA was stable for 60 days at 4 and 37°C and able to deliver PA in a sustained release manner over time. On macrophages, they exhibited no cell toxicity for a wide range of concentrations (from 1 to 100 µg/mL), demonstrating the safety of NC-PA. In addition, the nanoconjugate was efficiently taken up by RAW 264.7 cells over 6 hours reaching a maximum value after 3 hours of incubation. In conclusion, innovative nanoconjugates are a promising alternative to deliver drugs directly to the lungs and contributing to improving tuberculosis therapy.

Design of colloidal drug carriers of celecoxib for use in treatment of breast cancer and leukemia

Inflammation develops initiation and pathological process of cancer. Nanoscale drug carriers are required to be investigated for delivery of actives at cellular level for treatment of various cancer types. Solid lipid nanoparticles (CLX-SLN), nanostructured lipid carriers (CLX-NLC) and a nanoemulsion (CLX-NE) of celecoxib (CLX), a selective cyclooxygenase-2 inhibitor, were formulated for use in remedy of breast cancer and acute promyelocytic leukemia. The hot high pressure homogenization technique was employed to product formulations. Scanning electron micrographs were utilized for morphological characterization of formulations. Laser diffraction (LD), photon correlation spectroscopy (PCS) and differential scanning calorimetry (DSC) were used for examination of their physical stability by storing them at various temperatures. Drug release profiles of formulations were obtained. Their activity on cancer cells was investigated in the cell culture experiments. Stable formulations having homogenous size distribution were obtained below 200 nm with high drug payloads between 93.76% and 96.66%. Nanoparticles were ascertained to contribute controlled drug release. CLX-SLN induced the highest decrease in numbers of human breast cancer and human acute promyelocytic leukemia cells through the activation of the cell death cascades especially apoptosis in comparison to CLX-NLC, CLX-NE and the pure CLX application (p < 0.05). Nanoformulations of CLX optimized in this study were found to have various advantages expected from sophisticated drug delivery systems in order to achieve higher CLX efficiency at cellular level. Thus, they are able to be administered efficaciously alone and in combination therapies in remedy of breast cancer and acute promyelocytic leukemia.

Conjugated carbon quantum dots: Potent nano-antibiotic for intracellular pathogens

A common theme in the persistence of microbial infections involves intracellular survival of microbial pathogens within host cells where they stay sheltered from attack by antimicrobial agents. In order to improve antimicrobial access inside host cells, we developed nanoparticles intracellular delivery of antibiotics. Using an intracellular infection model with the periodontal pathogen, Porphyromonas gingivalis (P. gingivalis), we demonstrated significantly enhanced intracellular microbicidal activity with the standard antibiotic metronidazole (MET) through its conjugation onto 1–5 nm biocompatible nano-carrier, carbon quantum dot, which was derived from chlorophyll (cCQD). The conjugated cCQD-MET were rapidly internalized into the cultured cells, reaching almost 90% uptake within 3 h of the challenge. Our results consistently showed enhanced antimicrobial activity of the conjugate compared to MET alone. Even at concentrations as low as 0.26 µM, the conjugate showed 72% enhancement compared to the drug alone, resulting in significantly increased inhibition of intracellular P. gingivalis at lower antibiotic dosages. We achieved a high drug payload (80% w/w) on cCQD without affecting the potency of metronidazole as determined by cytotoxicity assays, cellular uptake of metronidazole, P. gingivalis invasion and elimination assays. The synthesized cCQD also displayed high fluorescence with 56% quantum yield at an absorbance peak of 380 nm and an emission peak of 480 nm, thus, allowing for fluorescence tracking and quantification of the drug intracellularly. A similar strategy may be used to repurpose other antibiotics for the treatment of intracellular bacterial infections.

New molecular therapies for the treatment of hearing loss.

An estimated 466 million people suffer from hearing loss worldwide. Sensorineural hearing loss is characterized by degeneration of key structures of the sensory pathway in the cochlea such as the sensory hair cells, the primary auditory neurons and their synaptic connection to the hair cells - the ribbon synapse. Various strategies to protect or regenerate these sensory cells and structures are the subject of intensive research. Yet despite recent advances in our understandings of the capacity of the cochlea for repair and regeneration there are currently no pharmacological or biological interventions for hearing loss. Current research focusses on localized cochlear drug, gene and cell-based therapies. One of the more promising drug-based therapies is based on neurotrophic factors for the repair of the ribbon synapse after noise exposure, as well as preventing loss of primary auditory neurons and regrowth of the auditory neuron fibers after severe hearing loss. Drug therapy delivery technologies are being employed to address the specific needs of neurotrophin and other therapies for hearing loss that include the need for high doses, long-term delivery, localised or cell-specific targeting and techniques for their safe and efficacious delivery to the cochlea. Novel biomaterials are enabling high payloads of drugs to be administered to the cochlea with subsequent slow-release properties that are proving to be beneficial for treating hearing loss. In parallel, new gene therapy technologies are addressing the need for cell specificity and high efficacy for the treatment of both genetic and acquired hearing loss with promising reports of hearing recovery. Some biomaterials and cell therapies are being used in conjunction with the cochlear implant ensuring therapeutic benefit to the primary neurons during electrical stimulation. This review will introduce the auditory system, hearing loss and the potential for repair and regeneration in the cochlea. Drug delivery to the cochlea will then be reviewed, with a focus on new biomaterials, gene therapy technologies, cell therapy and the use of the cochlear implant as a vehicle for drug delivery. With the current pre-clinical research effort into therapies for hearing loss, including clinical trials for gene therapy, the future for the treatment for hearing loss is looking bright.

827 CuxS-controlled chemotherapeutics release and photothermal- photodynamic therapeutic strategy to inhibit progression and metastasis of melanoma by eliciting immunogenic cell death

Conventional monotherapies only benefit a minority of melanoma patients while combined immunotherapy exhibited extremely high rates of treatment-related adverse events. Herein, we created a multifunctional and immunogenic nanoplatform, [email protected]2@DOX-CuxS-PEG, which integrating photothermal properties of gold nanoparticles, photodynamic properties of CuxS and chemotherapy into a single nanoplatform. Upon near-infrared laser irradiation (NIR), the CuxS were uncapped and triggered chemotherapy drugs release into tumor environment. The properties and cytotoxicity to melanoma cells were explored in vitro. In addition, the anti-tumor effect and molecular mechanism of inducing tumor-specific immune responses were also explored in vitro and in vivo. The nanoplatform was stabilized, facilely synthesized and exhibited a high drug payload up to 36.37±2.74%. Compared to control groups, the nanoplatform could forcefully inhibit tumor growth in situ (p<0.001) and lung metastasis with lower time and power intensity. Furthermore, it could promote maturation of dendritic cells and induce the infiltration of both CD8+and CD4+T lymphocytes in tumor in vivo. Mechanistically, the nanoplatform not only can eradicate cancer cells by inducing cell apoptosis and/or necrosis directly, but also induce a strong tumor-specific immune response by resulting in calreticulin exposure on the surface of cancer cell (p<0.01) and released high-mobility group box 1 (HMGB1) protein (p<0.01). Our study developed a promising NIR-triggered multifunctional and immunogenic nanocomposite, which could induce anti-tumor immunity and would be a potential strategy for melanoma in advanced stage.

Small Molecular Theranostic Assemblies Functionalized by Doxorubicin-Hyaluronic Acid-Methotrexate Prodrug for Multiple Tumor Targeting and Imaging-Guided Combined Chemo-Photothermal Therapy.

Because of high drug payload and minimized burden of foreign materials in the course of metabolism and excretion, carrier-free nanomedicine based on self-assembly of small-molecule therapeutic agents has attracted considerable attention in cancer therapy. However, obstacles still remained, such as lack of targeting efficiency, poor physiological stability, and serious drug burst release. Herein, we developed a self-dual-targeting prodrug conjugate by coupling methotrexate (MTX) and doxorubicin (DOX) to a hyaluronic acid (HA) backbone which enveloped the small molecular drug coassemblies of DOX and indocyanine green for specific targeting and imaging-guided chemo-photothermal therapy (PTT). The constructed nanosystems exhibited a diameter of ∼200 nm, superior physiological stability, and improved photothermal effect. Taking advantage of functionality of MTX-HA-DOX conjugate, the nanosystems remarkably enhanced the accumulation in the tumor regions by enhanced penetration and retention effect and CD44/folate receptor-mediated endocytosis. Upon the stimuli of acid, the nanosystems showed the rapid disassembly followed by the accelerated drug release. Consequently, the nanosystems demonstrated highly efficient apoptosis in cancer cells and remarkable tumor ablation by synergy between chemotherapy and PTT upon the irradiation of near-infrared laser. The multifunctional nanosystems based on small molecular theranostic assemblies could provide a promising potential in developing dual-targeting drug delivery and imaging-guided combinational therapy.

Light/pH-Triggered Biomimetic Red Blood Cell Membranes Camouflaged Small Molecular Drug Assemblies for Imaging-Guided Combinational Chemo-Photothermal Therapy.

Nanoparticles camouflaged by red blood cell (RBC) membranes have attracted considerable attention owing to reservation of structure of membrane and surface proteins, endowing prominent cell-specific function including biocompatibility, prolonged circulation lifetime, and reduced reticular endothelial system (RES) uptake ability. Considering the drawbacks of carrier-free nanomedicine including the serious drug burst release, poor stability, and lack of immune escape function, herein we developed and fabricated a novel RBC membranes biomimetic combinational therapeutic system by enveloping the small molecular drug coassemblies of 10-hydroxycamptothecin (10-HCPT) and indocyanine green (ICG) in the RBC membranes for prolonged circulation, controlled drug release, and synergistic chemo-photothermal therapy (PTT). The self-reorganized RBCs@ICG-HCPT nanoparticles (NPs) exhibited a diameter of ∼150 nm with core-shell structure, high drug payload (∼92 wt %), and reduced RES uptake function. Taking advantage of the stealth functionality of RBC membranes, RBCs@ICG-HCPT NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of near-infrared laser followed by acidic stimulation, RBCs@ICG-HCPT NPs showed exceptional instability by heat-mediated membrane disruption and pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with individual treatment, RBCs@ICG-HCPT NPs under dual-stimuli accomplished highly efficient apoptosis in cancer cells and remarkable ablation of tumors by chemo-PTT. This biomimetic nanoplatform based on carrier-free, small molecular drug coassemblies integrating imaging capacity as a promising theranostic system provides potential for cancer diagnosis and combinational therapy.

Hexahistidine-metal assemblies: A promising drug delivery system

It is of considerable interest to construct an ideal drug delivery system (i.e., high drug payload, minimal cytotoxicity, rapid endocytosis, and lysosomal escape) under mild conditions for disease treatment, tissue engineering, bioimaging, etc. Inspired by the coordinative interactions between histidine and metal ions, we present the facile synthesis of hexahistidine (His6)-metal assembly (HmA) particles under mild conditions for the first time. The HmA particles presented a high loading capacity, a wide variety of loadable drugs, minimal cytotoxicity, quick internalization, the ability to bypass the lysosomes, and rapid intracellular drug release. In addition, HmA encapsulation largely improved the antitumor ability of camptothecin (CPT) relative to free CPT. By capitalizing on these promising features in drug delivery, HmA will have great potential in various biomedical fields. Statement of SignificanceIt is of considerable interest to construct an ideal drug delivery system (i.e., high drug payload, minimal cytotoxicity, rapid endocytosis, and lysosomal escape) under mild conditions. Inspired by the coordinative interactions between histidine and metal ions, we present for the first time the facile synthesis of Hexahistidine (His6)-metal assembly (HmA) particles under mild conditions. The HmA particles exhibited a high loading capacity, a wide variety of loadable drugs, minimal cytotoxicity, quick internalization, the ability to bypass the lysosomes, and rapid intracellular drug release. By capitalizing on these promising features in drug delivery, HmA will have great potential in various biomedical fields.

A Facile Strategy to Generate High Drug Payload Celecoxib Micelles for Enhanced Corneal Permeability.

Topical ocular drug administration aimed at providing a high drug concentration at the precorneal site accompanied with enhanced corneal permeability to avoid systemic side effects is a very important therapeutic goal in ocular disorder therapy. In the present study, the solubility of the poorly soluble drug celecoxib (CXB) was significantly improved using a facile strategy to generate a high drug payload micellar formulation. By varying the drug/polymer feed ratios, the mean diameter of the formed CXB micelles ranged from 21.34 ± 0.23 to 28.53 ± 0.11 nm, and the drug loading capacity ranged from 4.31 to 15.87%. Transmission electron microscopy (TEM) showed that the formed CXB micelles had a uniform spherical morphology. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) were used to characterize the physicochemical properties of lyophilized CXB micelles. The obtained CXB micelles retained their properties through freeze-drying and rehydration, thereby providing long-term physicochemical stability over 3 months of storage at -20 °C. An in vitro release study showed that the CXB micelles released CXB in a sustained release manner without any apparent burst release over 72 h by the Higuchi non-Fickian diffusion mechanism. Notably, using corneas excised from rabbits, the in vitro corneal permeability of CXB from the micellar formulation was observed to be significantly greater than that of the microparticle formulation. Overall, the proposed micelles might be a promising vehicle for ophthalmic delivery of CXB with the significant enhancement of water solubility and corneal permeability.

In vitro and ex vivo assessment of microporous Faujasite zeolite (NaX-FAU) as a carrier for the oral delivery of danazol

Microporous zeolite NaX-FAU has been systemically evaluated for the oral delivery of the poorly water-soluble compound danazol. For this purpose, danazol-loaded zeolitic particles were prepared by the incipient wetness method and were characterized by means of N2 physisorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and high-resolution transmission electron microscopy (HRTEM). The zeolitic formulation shows a high drug payload and drug stability over a period of six months under accelerated storage conditions. The dissolution profile of danazol-loaded zeolitic particles was assessed in simulated gastric fluid (SGF) pH 1.2; fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) showing a gradual and increasing drug dissolution in the different media. Ex vivo studies using the everted gut sac model show an increased drug transport across rat intestinal epithelium when loaded in the zeolitic particles. Our results suggest that microporous Faujasite zeolite (NaX-FAU) could be used as a drug delivery system to facilitate the oral delivery of poorly water soluble compounds.

Aerosol technique-based carbon-encapsulated hollow mesoporous silica nanoparticles for synergistic chemo-photothermal therapy

Near-infrared (NIR)-responsive drug delivery systems have enhanced tumor ablative efficiency through permeation and retention effects. Graphene oxide (GO) has shown great potential both in photothermal therapy and in drug delivery. Thus, in this study, we designed an ambient spark-generated GO, wrapped on topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSN-NH2-TPT-CGO), to function as an efficient platform for pH-dependent sustained release of TPT. HMSN-NH2-TPT-CGO also exhibited a combined chemo-photothermal effect within a single carrier system. This developed system was stable with a uniform particle size (∼190 nm) and was demonstrated to possess a sufficient heat-absorbing capacity to induce tumor cell ablation. We performed the ablation of tumor cells both in vitro and in vivo in combination with photothermal therapy and chemotherapy using the spark-generated functional GO and HMSN. The prepared nanocarriers demonstrated high cellular uptake, apoptosis, and G0/G1 cell cycle arrest. In vivo study using the MDA-MB-231 xenograft model revealed the ultraefficient tumor ablative performance of HMSN-NH2-TPT-CGO compared with that of free TPT, with no toxic effect on vital organs. Altogether, the optimized nanocarriers presented a significant potential to act as a vehicle for cancer treatment. Statement of SignificanceThis is the first study that uses spark-generated graphene oxide nanoflakes to cover the topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSNs) to treat breast cancer. Dense silica was used as a hard template to prepare the HMSNs attributing to a high drug payload. The concentration of Na2CO3 was precisely controlled to minimize the silica etching time within 70 min. The use of the nanographene flakes served a dual purpose, first, by acting as a capping agent to prevent the premature release of drug and, second, by serving as a nano heater that significantly ablates the tumor cells. The prepared nanocarriers (NCs) exhibited effective and enhanced in vitro and in vivo apoptosis, as well as significant tumor growth inhibition even after 15 days of treatment time, with no toxic effect to the vital organs. The NCs enhanced in vitro tumor cell killing effects and served as an effective carrier for in vivo tumor regression, thereby highlighting the enormous potential of this system for breast cancer therapy.

Core-shell noble-metal@zeolitic-imidazolate-framework nanocarriers with high cancer treatment efficiency in vitro.

Core-shell Au@zeolitic-imidazolate-framework-8 (ZIF-8) nanostructures are reported as a nanocarrier with both a high drug payload and high cancer treatment efficiency in vitro. Impressively, when used as multifunctional drug delivery vehicles, such core-shell Au@ZIF-8 nanostructures not only exhibit light- and pH-controlled drug release properties, but also provide two synergetic therapeutic modes for cancer treatment, resulting in 98% cell-killing activity after 30 min light irradiation followed by 24 h incubation even though HeLa cells are treated only by Au@ZIF-8 nanostructures loaded with 10 μM doxorubicin hydrochloride. All these results demonstrate the promising applications of this type of core-shell nanostructure in biomedical fields.

His 6-Metal Assemblies: A Novel and Promising Drug Delivery System

Constructing an ideal drug delivery system (i.e., high drug payload, low cytotoxicity, and rapid endocytosis and lysosome escape) under mild conditions is of great interest in disease treatment, tissue engineering, bioimaging, etc. Inspired by the coordinative interactions between histidine and metal ions, we present for the first time the facile synthesis of His6-metal assemblies (HmA) particles under mild conditions. The HmA particles presented a high loading capacity, a wide variety of loadable drugs, low cytotoxicity, quick internalization and lysosomal escape and rapid intracellular drug release. In addition, HmA encapsulation greatly improved the antitumor ability of camptothecin (CPT) relative to free CPT. By capitalizing on these promising features in drug delivery, HmA should have great potential in various biomedical fields.

High drug payload nanoparticles formed from dexamethasone-peptide conjugates for the treatment of endotoxin-induced uveitis in rabbit.

PurposeTo develop and demonstrate the effectiveness of a novel dexamethasone (Dex) nanoformulation for treating uveitis.Materials and methodsWe designed and screened a dexamethasone-peptide conjugate (Dex-SA-FFFE), formed via a biodegradable ester bond linkage, that could spontaneously form high drug payload nanoparticles in aqueous solution for treating uveitis.ResultsAn in vitro release study indicated that Dex and Dex-SA-FFFE sustainably released from Dex-SA-FFFE nanoparticles over a 48 h study period. Meanwhile, the formed Dex-SA-FFFE nanoparticles hardly caused cytotoxicity in human corneal epithelial cell at drug concentrations up to 1 mM after 24 h of incubation but reduced cell viability after 48 h and 72 h of incubation. An in vitro anti-inflammatory efficacy assay showed that the Dex-SA-FFFE nanoparticles exhibited a comparable anti-inflammatory efficacy to that of Dex in lipopolysaccharide (LPS)-activated RAW264.7 macrophages via significant decreases in the secretion of various pro-inflammatory cytokines (e.g., nitric oxide, tumor necrosis factor-α, interleukin-6). Topical instillation of Dex-SA-FFFE nanoparticles showed good ocular tolerance without causing changes in corneal thickness and intraocular pressure during the entire study period. Furthermore, topical instillation of Dex-SA-FFFE nanoparticles displayed a comparable in vivo therapeutic efficacy to that of dexamethasone sodium phosphate (Dexp) aqueous solutions in an endotoxin-induced uveitis (EIU) rabbit model.ConclusionBased on these results, it is reasonable to believe that the proposed Dex-SA-FFFE nanoparticles might have great application for the treatment of anterior uveitis.