Preferential Oxycodone Loss of Physically Manipulated Abuse Deterrent Oxycodone HCl Extended Release Tablets Prepared for Nasal Insufflation Studies.

A method to reproducibly mill abuse deterrent oxycodone hydrochloride (HCl) extended release (ER) tablets was developed for a nasal insufflation pharmacokinetic (PK) study. Several comminution methods were explored before determining that a conical mill resulted in controlled milling of tablets to a size range equal to or below 1000 µm. However, milling resulted in significant loss of oxycodone from abuse deterrent oxycodone HCl ER tablets compared to minimal oxycodone loss from oxycodone HCl immediate release (IR) tablets. Characterization of milled tablet powder showed that loss of oxycodone was not attributed to analytical procedures or oxycodone phase change during high intensity milling processes. The content uniformity of oxycodone in the milled tablet powder varied when ER and IR tablets were milled to a particle size distribution equal to or below 500 µm but did not vary when particles were sized above 500 µm to equal to or below 1000 µm. In addition, the initial excipient weight to drug substance weight ratio impacted the amount of oxycodone lost from the respective formulation. However, dissolution demonstrated that when oxycodone HCl ER tablets are milled, differences in excipient weight to drug substance weight ratio and particle size distribution of milled tablets did not result in significantly different release of oxycodone.

Proton Oriented-"Smart Depot" for Responsive Release of Ca2+ to Inhibit Peptide Acylation in PLGA Microspheres.

PURPOSE: The purpose of this study was to characterize and detail the mechanism of a smart Ca2+ release depot (Ca3(PO4)2) about its ability for sustainable inhibition on peptide acylation within PLGA microspheres. METHODS: The octreotide acetate release and acylation kinetics were analyzed by RP-HPLC. Changes of Ca2+ concentration and adsorption behavior were determined by a Calcium Colorimetric Assay Kit. The inner pH changes were delineated by a classic pH sensitive probe, Lysosensor yellow/ blue® dextran. Morphological changes of microspheres, adsorption between polymer and additive, transformation of Ca3(PO4)2 were characterized using SEM, FTIR and SSNMR separately. RESULTS: Before and after microspheres formulation, the property and effectiveness of Ca3(PO4)2 were investigated. Compared with a commonly used calcium salt (CaCl2), high encapsulation efficiency (96.56%) of Ca3(PO4)2 guarantees lasting effectiveness. In an increasingly acidic environment that simulated polymer degradation, the poorly water-soluble Ca3(PO4)2 could absorb protons and transform into the more and more soluble CaHPO4 and Ca(H2PO4)2 to produce sufficient Ca2+ according to severity of acylation. The corresponding Ca2+ produce capacity fully met the optimum inhibition requirement since the real-time adsorption sites (water-soluble carboxylic acids) inside the degrading microspheres were rare. A sustained retention of three switchable calcium salts and slow release of Ca2+ were observed during the microsphere incubation. FTIR results confirmed the long-term inhibition effect induced by Ca3(PO4)2 on the adsorption between drug and polymer. CONCLUSIONS: With the presence of the smart Ca2+ depot (Ca3(PO4)2) in the microspheres, a sustainable and long-term inhibition of peptide acylation was achieved.

Preparation and Evaluation of Mosapride Citrate Dual-Release Dry Suspension.

In this paper, a novel formulation of dual-release dry suspension of mosapride citrate (DRDS-MC) was designed which can be quickly released in the stomach while having sustained-release effect. Co-grinding mixture of mosapride citrate (MC) together with L-HPC as hydrophilic excipient was prepared in order to improve the solubility of MC. The co-grinding mixture was characterized by solubility studies, DSC, X-RD, SEM, FTIR, and size distribution before the preparation of the DRDS-MC. Then, the co-grinding mixture was used to prepare DRDS-MC via wet granulation method. The evaluation of DRDS-MC was focused on physicochemical properties, intestinal absorption, and pharmacokinetics. The results of DSC, X-RD, SEM, FTIR, and size distribution indicated that MC resides in co-grinding mixture with no crystalline changes, hydrogen bonds made L-HPC greatly improving the solubility of MC. Then, the dissolution of DRDS-MC reached 70% in pH 1.2 within 2 h, and the 12-h dissolution of MC in pH 6.8 was nearly 80%. The sedimentation volume after 3 h was 0.94 and redispersibility was good. The linear regression equation between in vitro release of DRDS-MC and intestinal absorption fraction in rats was: Y = 29.215 + 47.535*X (r = 0.952). At last, pharmacokinetic studies in beagle dogs demonstrated that DRDS-MC has prolonged effect compared with commercial formulation Gasmotin as a reference. All results indicated that the DRDS-MC could be quickly released in the stomach while having sustained-release effect.

Design, synthesis and antiviral activity studies of schizonepetin derivatives.

A series of schizonepetin derivatives have been designed and synthesized in order to obtain potent antivirus agents. The antiviral activity against HSV-1 and influenza virus H3N2 as well as the cytotoxicity of these derivatives was evaluated by using cytopathic effect (CPE) inhibition assay in vitro. Compounds M2, M4, M5 and M34 showed higher inhibitory activity against HSV-1 virus with the TC50 values being in micromole. Compounds M28, M33, and M35 showed higher inhibitory activity against influenza virus H3N2 with their TC50 values being 96.4, 71.0 and 75.4 µM, respectively. Preliminary biological activity evaluation indicated that the anti-H3N2 and anti-HSV-1 activities improved obviously through the introduction of halogen into the structure of schizonepetin.

Copper-induced injectable hydrogel with nitric oxide for enhanced immunotherapy by amplifying immunogenic cell death and regulating cancer associated fibroblasts.

BACKGROUND: Immunogenic cell death (ICD) induced by different cancer treatments has been widely evaluated to recruit immune cells and trigger the specific antitumor immunity. However, cancer associated fibroblasts (CAFs) can hinder the invasion of immune cells and polarize the recruited monocytes to M2-type macrophages, which greatly restrict the efficacy of immunotherapy (IT). METHODS: In this study, an injectable hydrogel induced by copper (Cu) has been designed to contain antibody of PD-L1 and nitric oxide (NO) donor. The therapeutic efficacy of hydrogel was studied in 4T1 cells and CAFs in vitro and 4T1 tumor-bearing mice in vivo. The immune effects on cytotoxic T lymphocytes, dendritic cells (DCs) and macrophages were analyzed by flow cytometry. Enzyme-linked immunosorbent assay, immunofluorescence and transcriptome analyses were also performed to evaluate the underlying mechanism. RESULTS: Due to the absorbance of Cu with the near-infrared laser irradiation, the injectable hydrogel exhibits persistent photothermal effect to kill cancer cells. In addition, the Cu of hydrogel shows the Fenton-like reaction to produce reactive oxygen species as chemodynamic therapy, thereby enhancing cancer treatment and amplifying ICD. More interestingly, we have found that the released NO can significantly increase depletion of CAFs and reduce the proportion of M2-type macrophages in vitro. Furthermore, due to the amplify of ICD, injectable hydrogel can effectively increase the infiltration of immune cells and reverse the immunosuppressive tumor microenvironment (TME) by regulating CAFs to enhance the therapeutic efficacy of anti-PD-L1 in vivo. CONCLUSIONS: The ion induced self-assembled hydrogel with NO could enhance immunotherapy via amplifying ICD and regulating CAFs. It provides a novel strategy to provoke a robust antitumor immune response for clinical cancer immunotherapy.

Polydopamine-coated thalidomide nanocrystals promote DSS-induced murine colitis recovery through Macrophage M2 polarization together with the synergistic anti-inflammatory and anti-angiogenic effects.

High levels of proinflammatory cytokines, macrophage polarization status and immune-mediated angiogenesis play pivotal roles in the pathogenesis of inflammatory bowel disease (IBD). Thalidomide, an anti-inflammatory, immunomodulatory and antiangiogenic agent, is used off-label for treatment of IBD. The therapeutic potential of thalidomide is limited by its poor solubility and side effects associated with its systemic exposure. To address these issues and promote its therapeutic effects on IBD, thalidomide nanocrystals (Thali NCs) were prepared and coated with polydopamine (PDA), a potential macrophage polarization modulator, to form PDA coated Thali NCs (Thali@PDA). Thali@PDA possessed a high drug loading and displayed average particle size of 764.7 ± 50.30 nm. It showed a better anti-colitis effect than bare thalidomide nanocrystals at the same dose of thalidomide. Synergistic effects of polydopamine on anti-inflammatory and anti-angiogenic activities of thalidomide were observed. Furthermore, PDA coating could direct polarization of macrophages towards M2 phenotype, which boosted therapeutic effects of Thali@PDA on IBD. Upon repeated dosing of Thali@PDA for one week, symptoms of IBD in mice were significantly relieved, and histomorphology of the colitis colons were normalized. Key proinflammatory cytokine levels in the inflamed intestines were significantly decreased. Toxicity study also revealed that Thali@PDA is a safe formulation.

Molecular switch for the assembly of lipophilic drug incorporated plasma protein nanoparticles and in vivo image.

A strategy to manipulate the disulfide bond breaking triggered unfolding, and subsequently assembly of human serum albumin (HSA) in a lipophilic drug-dependent manner is present. In this study, the hydrophobic region, a molecular switch of the HSA, was regulated to form HSA-paclitaxel (HSA-PTX) nanoparticles by a facile route. High-resolution transmission electron microscopy and fluorescence quenching indicate that HSA coassembled with PTX, which acts as a bridge to form core-shell nanoparticles about 50-240 nm in size, and that PTX might bind to the subdomain IIA sites of HSA. Change of ultraviolet absorption and circular dichroism spectra reveal the formation of HSA-PTX nanoparticles, which is a safety, injectable pharmaceutic nanocarrier system for tumor target. This method to prepare nanocarrier systems for hydrophobic guest molecules reveals a general principle of self-assembly for other plasma proteins and other pharmacologically active substances with poor water solubility. It also provides a basis for developing nanocarrier systems for a wide range of applications in nanomedicine, from drug delivery to bioimaging systems.

Tumor immunotherapy boosted by R837 nanocrystals through combining chemotherapy and mild hyperthermia.

Melanoma is a malignant skin cancer that is prone to metastasis in the early stage and has a poor prognosis. Immunomodulatory therapy for melanoma has been a hot research topic in recent years. However, low immune cell infiltration and loss of tumor immunogenicity may occur in tumors, resulting in low response rates to immunotherapy. Thus, immunomodulatory therapy is usually used in combination with chemotherapy and radiotherapy. Development of combined therapeutic strategies with low systemic toxicity, high immune responsiveness and long-term inhibition of metastasis and recurrence of melanoma is the goal of current research. In this study, the insoluble immune adjuvant imiquimod (R837) was prepared as nanocrystals and coated with polydopamine (PDA) to form R837@PDA, which was then loaded into chitosan hydrogel (CGP) to form the drug-loaded gel system, R837@PDA@CGP (RPC), to combine immunomodulation effects, induction of immunogenic cell death (ICD) effects and immune-enhancement effects. After treatment with RPC, ICD in melanoma was induced, and the infiltration rate of cytotoxic T cells (CTLs) in melanoma was also significantly enhanced, which turned the tumor itself into an in situ vaccine and boosted the cancer-immunity cycle at the tumor site. Therefore, melanoma growth, metastasis and recurrence were notably inhibited.

Surface Decoration via Physical Interaction of Cupric Diethyldithiocarbamate Nanocrystals and Its Impact on Biodistribution and Tumor Targeting.

The vascular wall is the first physiologic barrier that circulating nanoparticles (NPs) encounter, which also is a key biological barrier to cancer drug delivery. NPs can continually scavenge the endothelium for biomarkers of cancer, and the chance of NPs' extravasation into the tumors can be enhanced. Here, we envision P-selectin as a target for specific delivery of drug nanocrystals to tumors. The cupric diethyldithiocarbamate nanocrystals (CuET NCs) were first prepared by an antisolvent method, and then nanocrystals were coated with fucoidan via physical interaction. The fucoidan-coated CuET nanocrystals (CuET@Fuc) possess high drug loading and have the ability to interact with human umbilical vein endothelial cells expressing P-selectin, which transiently enhances the endothelial permeability and facilitates CuET@Fuc extravasation from the peritumoral vascular to achieve higher tumor accumulation of drugs than bare CuET NCs. The CuET NC shows poorer anticancer efficacy than CuET@Fuc at the same dose of CuET. Upon repeated dosing of CuET@Fuc for 2 weeks, no mortality was observed in treated melanoma-bearing mice, while the mortality in the control group and excipient-treated groups reached 23%. The growth rate of melanoma in the CuET@Fuc-treated group was significantly lower than those in other groups. Furthermore, an acute toxicity study revealed that CuET@Fuc is a safe formulation for cancer treatment.

One Single Site Clinical Study: To Evaluate the Safety and Efficacy of Immunotherapy With Autologous Dendritic Cells, Cytokine-Induced Killer Cells in Primary Hepatocellular Carcinoma Patients.

Dendritic cells (DCs) and cytokine-induced killer (CIK) cells play an important role in the anti-tumor immune response. In this study, we evaluated the clinical effectiveness of DC/CIK-CD24 immunotherapies to primary hepatocellular carcinoma patients who received radical resection. 36 resected primary hepatocellular carcinoma (HCC) patients were enrolled from August 2014 to December 2015. All patients received two or four times of DC/CIK immunotherapy after radical resection. 1-4 years patients' survival rates were evaluated during the follow-up. The 4-year survival rate of patients who received two times of immunotherapy was 47.1%, and the rate of those who received four times of immunotherapies was 52.6%. Compared to baseline, after receiving the DC/CIK-CD24 autotransfusion, the serum Treg concentration of the patients decreased, while CD3+, CD4+, CD56+ increased slightly. The adverse effect of immunotherapy was I-II° transient fever and could be tolerable. DC/CIK-CD24 immunotherapy can delay the relapse time.

A novel nanoparticle drug delivery system based on PEGylated hemoglobin for cancer therapy.

Proteins such as albumin, gelatin, casein, transferrin, and collagen are widely used as drug delivery systems. However, only albumin-based paclitaxel (PTX) formulation Abraxane® (PTX-albumin NPs prepared by nab-technology) has been successfully developed for treating metastatic breast cancer clinically due to abundant materials, simple industrial scale-up process, and well tumor-targeting ability. Hemoglobin (Hb) is another protein used for drug delivery with similar advantages. In this study, we successfully synthesized PEG-Hb nanoparticles loading with PTX based on previously well-established acid-denatured method. PEG-Hb-PTX NPs showed enhanced cellular uptake and great cellular inhibition ability in vitro. Moreover, our animal study showed that PEGylated NPs greatly accumulated in tumor tissues and exhibited excellent anticancer activity in vivo. We found that PEG-Hb-PTX NPs possess a better in vivo antitumor effect than the commercially available Taxol® formulation. We believe that PEG-Hb has great potential as an efficient drug delivery system for further clinic study.

Effect of inner pH on peptide acylation within PLGA microspheres.

Polymer degradation within the controlled-release depots comprising of lactide and glycolide (PLGA) forms an acidic microenvironment, in which severe acylation of the peptide by the polymer degradation products takes place. The aim of this study was to make out the role of the inner µpH on peptide acylation within the microspheres and how could it influence the reaction. The effects of pH on the acylation reaction within microspheres were composed of two aspects. Firstly, the inherent effect of pH on the acylation reaction itself was figured out: with the pH environment going up from acid to neutral, a model peptide (octreotide acetate) acylation became more and more serious. Then, the multivariate effect of pH on the dynamic microsphere delivery system especially the state of the acylation substrates (drug and oligomer) was investigated. When the inner pH was neutralized by Ca(OH)2 to varying degrees, polymer degradation rate, drug release rate, polymer degradation mechanism and oligomer accumulation state within the microspheres all changed. These changes highly affected the mass transfer of the acylation substrates to the external release medium. Neutralization of the µpH prolonged the retention time of drug and oligomer within the microspheres. Water absorption and single microsphere swelling experiments all showed a higher retention amount of acylation substrates during the critical period for peptide acylation. Generally, when the inner µpH was neutralized, except that the neutral environment itself promoted acylation reaction, the effects of pH on the dynamic system were also highly responsible for the serious acylation within the microspheres.

A modified hydrophobic ion-pairing complex strategy for long-term peptide delivery with high drug encapsulation and reduced burst release from PLGA microspheres.

Poor encapsulation and high initial burst were two major obstacles for the water-soluble peptide drug loaded microspheres preparation using the industrial emulsification method. In the present study, we hypothesized that the hydrophobic ion-pairing (HIP) complex strategy with a further healing of the pores within the microspheres may improve drug encapsulation and initial burst release. DSS was chosen as the most suitable one among the three test ion-pairing agents (SDS, DSS and STC) due to its high binding efficiency with drug and reversible dissociation capacity in presence of counter ions. The formation of HIP complex between octreotide acetate and DSS successfully reversed the highly water-soluble nature of the drug. A specific S/O/W method was adopted to encapsulate such drug containing HIP complex. The encapsulation efficiency of the drug was greatly improved compared with the conventional W1/O/W2 method (from 44% to 90%). Under the optimal healing conditions (the healing time 6 h, temperature 40 °C and 4% DEP content), the pores within the microspheres were effectively healed. Initial burst amount of octreotide acetate in S/O/W microspheres decreased to 3.56%. The pore healing effect was further confirmed by the scanning electron microscopy and fluorescence microscopy results. In the process of testing the drug release performance of such new strategy in vitro and in vivo, a more satisfactory single phase release profile with sustained and steady drug release was observed. These results suggested that the modified HIP strategy could be a promising platform for water-soluble peptide encapsulation with high encapsulation efficiency, low initial burst and stable drug release mechanism.

A switchable NO-releasing nanomedicine for enhanced cancer therapy and inhibition of metastasis.

Clinical chemotherapy for cancer is limited by the physiological barrier of tumors, resulting in low drug delivery to tumors, poor efficacy of drugs and inability to block tumor metastasis. Here we developed an intelligent switchable nitric oxide (NO)-releasing nanoparticle, IPH-NO, which loads a photosensitizer (IR780) and the chemotherapy drug paclitaxel (PTX) into NO donor-S-nitrosated human serum albumin (HSA-NO). NO exhibits two effects based on its concentration: enhancement of chemotherapy by increasing the enhanced permeability and retention (EPR) effect at low concentrations and direct killing of cancer cells at high concentrations. IPH-NO can slowly release NO in the presence of glutathione to boost tumor vascular permeability and improve drug accumulation. Near-infrared light irradiation was utilized to induce a quick release of NO that can directly kill cancer cells at high concentrations. This combination of phototherapy and NO gas therapy activated by NIR together with chemotherapy showed significant effects in tumor inhibition. Furthermore, IPH-NO blocked tumor metastasis by inhibiting epithelial mesenchymal transition. PH-NO provides a novel strategy to control NO release at tumor site for drug accumulation and combination therapies, consequently potentiating the anticancer efficacy and inhibiting tumor metastasis.

Starvation-amplified CO generation for enhanced cancer therapy via an erythrocyte membrane-biomimetic gas nanofactory.

Carbon monoxide (CO)-based gas therapy has emerged as an attractive therapeutic strategy for cancer therapy. However, the main challenges are the in situ-triggered and efficient delivery of CO in tumors, which limit its further clinical application. Herein, we developed an erythrocyte membrane-biomimetic gas nanofactory (MGP@RBC) to amplify the in situ generation of CO for combined energy starvation of cancer cells and gas therapy. This nanofactory was constructed by encapsulating glucose oxidase (GOx) and Mn2(CO)10 (CO-donor) into the biocompatible polymer poly(lactic-co-glycolic acid), obtaining MGP nanoparticles, which are further covered by red blood cell (RBC) membrane. Because of the presence of proteins on RBC membranes, the nanoparticles could effectively avoid immune clearance in macrophages (Raw264.7) and significantly prolong their blood circulation time, thereby achieving higher accumulation at the tumor site. After that, the GOx in GMP@RBC could effectively catalyze the conversion of endogenous glucose to hydrogen peroxide (H2O2) in the presence of oxygen. The concomitant generation of H2O2 could efficiently trigger CO release to cause dysfunction of mitochondria and activate caspase, thereby resulting in apoptosis of the cancer cells. In addition, the depletion of intratumoral glucose could starve tumor cells by shutting down the energy supply. Altogether, the in vitro and in vivo studies of our synthesized biomimetic gas nanofactory exhibited an augmentative synergistic efficacy of CO gas therapy and energy starvation to inhibit tumor growth. It provides an attractive strategy to amplify CO generation for enhanced cancer therapy in an accurate and more efficient manner. STATEMENT OF SIGNIFICANCE: Carbon monoxide (CO) based gas therapy has emerged as an attractive therapeutic strategy for cancer therapy. In this study, we developed an erythrocyte membrane biomimetic gas nanofactory to amplify the in-situ generation of CO for combined cancer starvation and gas therapy. It is constructed by coating glucose oxidase (GOx) and CO donor-loaded nanoparticles with erythrocyte membrane. Due to the erythrocyte membrane, it can effectively prolong blood circulation time and achieve higher tumor accumulation. After accumulated in tumor, endogenous glucose can be effectively catalyzed to hydrogen peroxide, in-situ amplified CO release to induce the apoptosis of cancer cells. In addition, depleting glucose can also starve tumor cells by shutting down the energy supply. Overall, our biomimetic gas nanofactory exhibits an augmentative synergistic efficacy of CO gas therapy and starvation to increased tumor inhibition. It provide a novel strategy to deliver CO in an accurate and more efficient manner, promising for combined cancer therapy in future clinical application.

Sodium tanshinone IIA sulfonate attenuates cardiac dysfunction and improves survival of rats with cecal ligation and puncture-induced sepsis.

Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg-1), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.

Exploring intracellular fate of drug nanocrystals with crystal-integrated and environment-sensitive fluorophores.

Formulating a poorly water-soluble drug substance into nanocrystals offers many advantages. Understanding of the in vivo fate of drug nanocrystals is however very limited. In this study, we utilized the hybrid nanocrystal concept and studied the kinetic process of dissolution in cancer cells. By taking advantage of aggregation-induced emission (AIE), hybrid paclitaxel (PTX) nanocrystals integrated with tetraphenylethene (TPE) enabled a novel way for estimating the intracellular dissolution process of the nanocrystals. When TPE is entrapped in a nanocrystal, fluorescence is emitted when the nanocrystal is optically excited. When an entrapped TPE molecule is released to a liquid medium due to the dissolution of the nanocrystal, its fluorescence is quenched. By monitoring the change in fluorescence, it is possible to quantify the dissolution of nanocrystals in a biological environment. Cellular uptake studies of hybrid nanocrystals were conducted with KB and HT-29 cell lines and characterized by confocal microscopy, flow cytometry, and HPLC. The results suggest that drug nanocrystals were taken up directly by the cells, and subsequently dissolved in the cytoplasm. The extent to which the drug nanocrystal dissolved was estimated according to the fluorescence measurement. The cellular uptake and intracellular dissolution could be influenced by drug concentration, incubation time, and surface coating, as well as the type of cell line.

Enhanced hepatic targeting, biodistribution and antifibrotic efficacy of tanshinone IIA loaded globin nanoparticles.

Tanshinone IIA (TA) has been recently used to treat liver diseases. However, the poor water solubility and fast metabolism obstruct TA in to be used for the treatment of liver diseases. To overcome this, TA was encapsulated into globin to form nanoparticles (TA-Gb-NPs) by our self-assembling method. We evaluated their biodistribution, pharmacokinetics, targeting ability to liver and antifibrotic effects. As a result, TA-Gb-NPs had a good hepatic targeting ability and achieved higher concentration and longer retention in liver than tanshinone IIA suspension (TA-S). Compared with TA-S, TA-Gb-NPs significantly improved serum biochemical parameters in thioacetamide (TAA) induced liver fibrosis mouse model. Furthermore, histological analysis of mouse liver slices revealed that TA-Gb-NPs could markedly reduce the fibrosis scores and attenuate the progression of the hepatic fibrosis. In conclusion, the TA-Gb-NPs may be a good candidate for the treatment of hepatic fibrosis.

Replacing heme with paclitaxel to prepare drug-loaded globin nanoassembles for CD163 targeting.

Protein-based nanoparticles hold great promises in both preclinical and clinical practices, such as oncology diagnosis and treatment, because of their high biocompatibility and biodegradability. However, the complicated preparation and lack of targeting specific cells or tissues may limit their further uses. To overcome these limitations, we developed a novel replacing method for preparing dual-functional protein nanocarrier, such that one function is capable of encapsulating small molecule into protein, whereas the other function is cable of recognizing CD163 receptor [hemoglobin (Hb) scavenger receptor]. In this study, Hb was chosen as the targeting drug carrier. First, the heme group in the Hb was removed and replaced by paclitaxel (PTX) to form nanoparticles (Gb-NPs-PTX). The resulted Gb-NPs-PTX showed spherical shape and their diameter could be controlled in the range of 120-160 nm by altering the ratio of PTX to Hb. The binding activity of Gb-NPs-PTX to CD163 was confirmed by cell uptake in CD163(+) Chinese hamster ovary cells. Results in vivo also showed a CD163-dependent tissue accumulation of Gb-NPs-PTX in mice. In summary, by using the novel replacing method, PTX could be easily encapsulated into Hb nanoparticles and the targeting effects of Hb could also be kept.

Enhanced brain targeting of curcumin by intranasal administration of a thermosensitive poloxamer hydrogel.

OBJECTIVES: The aim of this study was to develop a curcumin intranasal thermosensitive hydrogel and to improve its brain targeting efficiency. METHODS: The hydrogel gelation temperature, gelation time, drug release and mucociliary toxicity characteristics as well as the nose-to-brain transport in the rat model were evaluated. KEY FINDINGS: The developed nasal hydrogel, composed of Pluronic F127 and Poloxamer 188, had shorter gelation time, longer mucociliary transport time and produced prolonged curcumin retention in the rat nasal cavity at body temperature. The hydrogel release mechanism was diffusion-controlled drug release, evaluated by the dialysis membrane method, but dissolution-controlled release when evaluated by the membraneless method. A mucociliary toxicity study revealed that the hydrogel maintained nasal mucosal integrity until 14 days after application. The drug-targeting efficiencies for the drug in the cerebrum, cerebellum, hippocampus and olfactory bulb after intranasal administration of the curcumin hydrogel were 1.82, 2.05, 2.07 and 1.51 times that after intravenous administration of the curcumin solution injection, respectively, indicating that the hydrogel significantly increased the distribution of curcumin into the rat brain tissue, especially into the cerebellum and hippocampus. CONCLUSIONS: A thermosensitive curcumin nasal gel was developed with favourable gelation, release properties, biological safety and enhanced brain-uptake efficiency.