Journal of Drug Targeting (J Drug Target)

Publications in this journal

• Article: Necrosis affinity evaluation of (131)I-hypericin in a rat model of induced necrosis.

  Ming Kong, Jian Zhang, Cuihua Jiang, Xiao Jiang, Yue Li, Meng Gao, Nan Yao, Dejian Huang, Xiaoning Wang, Zhijun Fang, Wei Liu, Ziping Sun, Yicheng Ni
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  ABSTRACT: Abstract Cancers are often with spontaneous or therapeutic necrosis that could be utilized as a generic target for developing new treatments. The purpose of this study was to investigate the biodistribution and pharmacokinetics of radioiodinated hypericin (Hyp), a naturally occurring compound, after intravenous (i.v.) injection in a rat model of liver and muscle necrosis (n = 42), and evaluate its necrosis affinity. Hyp was labeled with (131)I with labeling efficiency >99%. After incubating in solution/rat plasma for 8 days, radiochemical purity of (131)I-Hyp remained 98.1 and 97.1%, respectively, indicating good in vitro stability. SPECT-CT images at 24 h after i.v. injection of (131)I-Hyp in rats with induced liver and muscle necrosis showed obvious tracer absorption in necrotic tissues. Biodistribution studies revealed that the percentage of the injected dose per gram of tissue (%ID/g) evolved from 1.9 %ID/g at 6 h, through a maximum 3.0 %ID/g at 12 h, to 1.0 %ID/g at 192 h in necrotic liver. Pharmacokinetics studies revealed that the terminal elimination half-life, total body clearance and area under the curve of (131)I-Hyp were 32.7 h, 9.2 L/h/kg and 1.6 MBq/L*h, respectively. These results demonstrated that (131)I-Hyp features a long blood circulation in animals and persistent retention in necrotic tissues. Therefore, (131)I-labeled Hyp could be a broad-spectrum anti-tumor agent with a cost much cheaper relative to the biological agents such as monoclonal antibodies.
  Journal of Drug Targeting 04/2013;
• Article: Renal interstitial permeability changes induced by microbubble-enhanced diagnostic ultrasound.

  Peijing Li, Yunhua Gao, Jihang Zhang, Zheng Liu, Kaibin Tan, Xing Hua, Jinling Gong
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  ABSTRACT: Abstract Ultrasound-targeted microbubble (MB) destruction (UTMD) has been shown to increase the glomerular permeability, providing a potential novel therapeutic approach in targeted drug release for kidney diseases. Therefore, we investigated the impact of UTMD on renal interstitial permeability using MB-mediated diagnostic ultrasound (DUS). The left kidney of Sprague-Dawley (SD) rat was insonated by UTMD with either continuous or intermittent mode for 5 min. Evans blue (EB) revealed that both modes induced renal vascular permeability increase after DUS but recovered after 24 h. Intermittent insonation caused more severe injury than continuous mode. Red blood cells leaked out of the capillaries into interstitium without glomerular capillary hemorrhage (GCH) by hematoxylin and eosin (HE) staining. Electronic microscopy revealed the disruption of focal capillary wall in interstitial tissues. Morphological results confirmed capillary wall recovered in 24 h post-treatment. Results from fluorescence-labeled MBs showed that MBs were mainly localized in the interstitial portion of the tubular region and retained at 24 h. Intriguingly, urinalysis showed no clinical proteinuria after treatment. Our results indicated that MB plus DUS specifically and reversibly enhanced the interstitial permeability without affecting glomerulus, which may be developed into a therapeutic approach for targeting drug release to individual renal compartments.
  Journal of Drug Targeting 04/2013;
• Article: Fine needle aspiration biopsy proves increased T-lymphocyte proliferation in tumor and decreased metastatic infiltration after treatment with doxorubicin bound to PHPMA copolymer carrier.

  Jaroslav Betka, Ondrej Hovorka, Jan Boucek, Karel Ulbrich, Tomas Etrych, Blanka Rihova
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  ABSTRACT: Abstract Introduction: Fine needle aspiration biopsy (FNAB) is an easy method with an option of repetitive withdrawal of cell material. Methods: First, mice were inoculated with mouse T-lymphoma, after 10 d the samples from tumor, lymph nodes and spleen gained by FNAB and excision were analyzed by flow cytometry. Tumor progression was compared to the control group simultaneously. Then, 10 d after tumor cell inoculation free doxorubicin (DOX) or different PHPMA DOX conjugates were injected. Cell material was analyzed to detect subpopulations of lymphocyte infiltrate, and levels of cytokines in correlation with progression or regression of the disease. Results: FNAB has no influence on the tumor's growth or survival of experimental animals. After treatment with PHPMA conjugates there was a significant increase of T-lymphocyte subpopulations in tumor microenvironment compared to controls or free DOX, but only in mice with confirmed macroscopic regression of tumor within two weeks. Mice treated with conjugates showed significantly lower cancer infiltration of lymph nodes and spleen. Conclusion: FNAB provides a great benefit to in vivo monitoring of cell changes directly in the tumor after treatment. The number of infiltrating T-lymphocytes increases in correlation with consecutive tumor eradication after treatment with PHPMA. This proves that not only direct cytotoxic but also imunostimulating effect are necessary for successful treatment.
  Journal of Drug Targeting 04/2013;
• Article: Nanocarriers for oral drug delivery.

  Lin Zhang, Shuli Wang, Manhong Zhang, Jie Sun
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  ABSTRACT: Abstract The oral route for delivery of pharmaceuticals is widely used and accepted. However, many biological therapeutics that have poor solubility, poor permeability, and/or poor stability in the gastrointestinal environment have poor oral bioavailability and are therefore rarely used for oral drug delivery. In recent years, nanocarriers are widely used, which can provide an alternative solution for oral administration of these drugs. In this article, several nanocarriers (nanoparticles, micelles, liposomes, nanocrystals, carbon nanotubes, nanoemulsions, dendrimers, and nanospheres) for drug delivery systems have been designed based on different nanomaterials for oral drug delivery.
  Journal of Drug Targeting 04/2013;
• Article: The application of nanoemulsion in dermatology: an overview.

  Yan Wu, Yuan-Hong Li, Xing-Hua Gao, Hong-Duo Chen
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  ABSTRACT: Abstract Nanotechnology has been introduced into dermatology for years. Nanoemulsions (NEs) are promising drug delivery systems with practical applications for pharmaceutical, cosmetic and chemical industry applications. Herein, we provide an overview of the application of NEs in dermatology during the latest 5 years. We reviewed the antioxidants in NEs form, non-steroidal anti-inflammatory drug loaded by NE, NEs in photodynamic therapy, NEs in decontamination of radionuclides, antimicrobial NEs, NEs carrying lipids, NEs containing Octyl Methoxycinnamate, et al. NEs demonstrate good stability, stable physical and chemical properties. NEs are able to enhance the functionality and efficacy of active chemicals and natural ingredients. NEs exhibit great application potential in the field of dermatology.
  Journal of Drug Targeting 04/2013;
• Article: The receptor binding fragment of alpha-fetoprotein is a promising new vector for the selective delivery of antineoplastic agents.

  Galina A Posypanova, Vladimir A Makarov, Mariya V Savvateeva, Anastasiya V Bereznikova, Evgeny S Severin
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  ABSTRACT: Abstract The alpha-fetoprotein (AFP) binding protein, a putative AFP receptor, is a tumour marker that is present on the surfaces of malignant cells. AFP enters cells through receptor-mediated endocytosis. The recombinant C-terminal fragment of AFP (AFP-3BC, which consists of amino acid residues 473-596) was obtained by the expression in Escherichia coli. AFP-3BC was shown to be bound specifically to the AFP putative receptor on tumour cells and accumulated by endocytosis in these cells in a similar manner to that of full-length human AFP. In lymphocytes, the binding and endocytosis of AFP-3BC were absent. Thus, the AFP receptor binding site was shown experimentally to be located within the AFP-3BC sequence. A conjugate of synthesised AFP-3BC with the antitumour antibiotic doxorubicin (DOX-AFP-3BC) demonstrated high antitumour activity in vitro. Thus, AFP-3BC can be used successfully as a vector for the targeted selective delivery of drugs into tumour cells.
  Journal of Drug Targeting 04/2013;
• Article: Therapeutic effect of liposomal-N-acetylcysteine against acetaminophen-induced hepatotoxicity.

  Misagh Alipour, Caroline Buonocore, Abdelwahab Omri, Mary Szabo, Kresimir Pucaj, Zacharias E Suntres
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  ABSTRACT: Abstract Background: Acetaminophen (APAP) is an antipyretic analgesic drug that when taken in overdose causes depletion of glutathione (GSH) and hepatotoxicity. N-acetylcysteine (NAC) is the antidote of choice for the treatment of APAP toxicity; however, due to its short-half-life repeated dosing of NAC is required. Purpose: To determine whether a NAC-loaded liposomal formulation (Lipo-NAC) is more effective than the conventional NAC in protecting against acute APAP-induced hepatotoxicity. Methods: Male Sprague-Dawley rats were challenged with an intragastric dose of APAP (850 mg/kg b.wt.); 4 h later, animals were administered saline, NAC, Lipo-NAC or empty liposomes and sacrificed 24 h post-APAP treatment. Results: APAP administration resulted in hepatic injury as evidenced by increases in plasma bilirubin, alanine (AST) and aspartate (ALT) aminotransferase levels and tissue levels of lipid peroxidation and myeloperoxidase as well as decreases in hepatic levels of reduced GSH, GSH peroxidase and GSH reductase. Treatment of animals with Lipo-NAC was significantly more effective than free NAC in reducing APAP-induced hepatotoxicity. Histological evaluation showed that APAP caused periacinar hepatocellular apoptosis and/or necrosis of hepatocytes around the terminal hepatic venules which was reduced by NAC treatment, the degree of reduction being greater for Lipo-NAC. Conclusion: These data suggest that administration of Lipo-NAC ameliorated the APAP-induced hepatotoxicity.
  Journal of Drug Targeting 04/2013;
• Article: Delivery of hydrophilic drug doxorubicin hydrochloride-targeted liver using apoAI as carrier.

  Yuan Yuan, Weina Wang, Baolong Wang, Haiyan Zhu, Boheng Zhang, Meiqing Feng
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  ABSTRACT: Abstract High-density lipoprotein (HDL) particles can deliver cholesterol from peripheral tissues to the liver through apolipoprotein A1 (Apo A1), which specifically binds to the scavenger receptor class B type 1 (SR-B1) receptor on the surface of hepatocytes. Therefore, ApoA1 can be potentially used to target drugs to the liver. In this study, we successfully loaded doxorubicin hydrochloride (Dox or Dox-HCl), which is a hydrophilic drug used in a wide variety of clinical applications, into the core of reconstituted HDL (rHDL prepared by apoAI and egg phospholipids) to form a doxorubicin-HDL complex (rHDL-Dox). The MTT assays showed that rHDL-Dox particles also had higher cytotoxicity against several cells lines compared to free drug or Dox encapsulated into liposomes. A cellular uptake assay demonstrated that rHDL-Dox had higher absorption in SR-BI receptor positive liver cells. Importantly, in vivo experiments showed that rHDL-Dox can reduce tumor growth more effectively than liposomes. In addition, an in vitro hemolysis assay showed that rHDL-Dox caused only limited hemolysis in the case of high doses. Taken together, our findings indicate that rHDL is a safe and effective drug delivery system for targeting liver.
  Journal of Drug Targeting 04/2013;
• Article: Development and characterization of nanolipobeads-based dual drug delivery system for H. Pylori targeting.

  Ashish Kumar Jain, Sunil Kumar Jain
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  ABSTRACT: Abstract The objective of the present investigation was to prepare and evaluate nanolipobeads which permit the targeting of drugs to H. Pylori and potentially used for the treatment of gastric ulcer. For this polyvinyl alcohol nanoparticles were prepared by freeze thaw cyclizing method and surface acylation was done by treating with (1M) palmitoyl chloride in hexane followed by addition of 0.1 N NaOH to induce acylation by adjusting pH below 6.5. Finally, nanolipobeads synthesis was carried out by combining equal parts of suspension of acylated poly vinyl alcohol nanoparticles (PVA-NPs) and AMOX encapsulated PE liposomes suspension. The uniformity of supported PE lipid layer on acylated PVA-NPs was examined using fluorescence and confocal laser scanning electron microscopy. The optimized nanolipobeads formulation demonstrated 773.3 ± 4.3 nm average age size and 84.7 ± 2.9% of AMOX and 67.5 ± 2.8% of RBC release up to 72 h, respectively. Furthermore, binding specificity and targeting propensity toward H. pylori (SKP-56) was confirmed by agglutination and in situ adherence assay. Reduction of the absolute alcohol induced ulcerogenic index from 3.01 ± 0.25 to 0.31 ± 0.09 and 100% H. pylori clearance rate was observed. These results suggested that nanolipobeads are potential vector for development of dual drug delivery for effective treatment of H. pylori associated peptic ulcer.
  Journal of Drug Targeting 04/2013;
• Article: Octreotide-mediated tumor cell uptake and intracellular pH-responsive drug delivery of the self-assembly supramolecular nanocarrier.

  Jiangxiu Niu, Aiwen Huang, Yanyu Xiao, Zhigui Su, Hongying Li, Qineng Ping, Xiao Bao, Sai Li, Yinan Chen, Mingjie Sun
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  ABSTRACT: Abstract In this study, DOX-loaded supramolecular nanocarrier (DLSC) was assembled by using two new amphiphilic polymers, octreotide-polyethylene glycol monostearate (OPMS) and N-octyl-N-succinyl O-carboxymethyl chitosan (OSCC). The characteristics of the DLSC were investigated. The results indicated that the significant pH-triggered release in vitro. The cellular uptake of DLSC was much higher than that of DOX-loaded OSCC micelles (DLOM) in the SMMC-7721 (somatostatin receptor (SSTR) over-expressed cell) cells, which suggested the SSTR-mediated properties. A considerable amount of drug entered the nucleus due to the pH-triggered deformation of the supramolecular structure and rapid release of drug in acidic endosomes of tumor cells. The killing efficacy was much higher than that of DLOM in the SMMC-7721. In S180 sarcoma-bearing KM mice, the biodistribution and therapeutic activity were studied. DLSC showed extended circulation time in plasma, decreasing drug concentrations in the heart and accumulating drug concentrations in the pancreas and tumor. In addition, minimized weight changes and cardiac toxicity, high suppression ratio of tumor growth and longer survival time were observed after intravenous injection of DLSC. The studies suggested that the supramolecular nanocarrier constructed of different designated polymers with multiple functions would be one of the most effective approaches for active targeting drug delivery.
  Journal of Drug Targeting 04/2013;
• Article: Injectable and biodegradable poly(organophosphazene) hydrogel as a delivery system of docetaxel for cancer treatment.

  Jung-Kyo Cho, Ji Min Hong, Taesu Han, Han-Kwang Yang, Soo-Chang Song
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  ABSTRACT: Abstract Although docetaxel (DTX) is an advanced taxoid, further augmentation of its properties is still required, such as improvement in its low aqueous solubility. Herein, we report the development of biodegradable/injectable poly(organophosphazene) (PPZ) hydrogels for the delivery of DTX without the use of organic solvents. An aqueous solution of PPZ containing α-amino-ω-methoxy-poly(ethylene glycol) (AMPEG) 750 instead of AMPEG 550 was prepared, thereby increasing the erosion capacity of the hydrogel by judicious balance of the hydrophobic/hydrophilic moieties. The safety of the hydrogel was demonstrated using a biocompatibility test. The PPZ aqueous solution (8 wt%) containing DTX exhibited a thermosensitive sol-gel-sol transition that was independent of the concentration of DTX (1-3 mg/mL). The in vitro release study indicated that the dominant release mechanism was either erosion or diffusion/erosion-controlled release depending on the DTX content of the hydrogel. The in vivo anticancer effect of the intratumorally injected PPZ system in human gastric cancer cell-xenografted mice was evaluated, which demonstrated a significantly (p < 0.01) enhanced effect of the DTX-PPZ hydrogel system compared to the control (DTX solution, i.v.). In conclusion, the PPZ hydrogel may be a promising candidate for DTX delivery, affecting a decrease in the size of tumors with little toxicity prior to exeresis.
  Journal of Drug Targeting 04/2013;
• Article: Anionic polymer-coated lipoplex for safe gene delivery into tumor by systemic injection.

  Yoshiyuki Hattori, Haruka Yamasaku, Yoshie Maitani
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  ABSTRACT: Abstract In this study, we developed an anionic lipoplex by coating cationic lipoplex with anionic polymers such as hyaluronan (HA), chondroitin sulfate C (CS) and poly-l-glutamic acid (PLE) to deliver the plasmid DNA efficiently into the tumor by avoiding interaction with erythrocytes. The sizes of HA-, CS- and PLE-coated lipoplexes were ∼200 nm and the ζ-potentials were negative. CS- and PLE-coated lipoplexes did not induce agglutination after mixing with erythrocytes, but cationic and HA-coated lipoplexes exhibited agglutination. In terms of biodistribution and gene expression after intravenous administration, cationic and HA-coated lipoplexes largely accumulated and induced gene expression in the lung. In contrast, CS- and PLE-coated lipoplexes did not exhibit high gene expression in the lung and mainly accumulated in the liver. However, in tumor, differences in lipoplex accumulation and gene expression were not observed among the lipoplexes. In terms of toxicity after intravenous injection, CS- and PLE-coated lipoplexes did not increase tumor necrosis factor-α, aspartate aminotransferase and alanine aminotransferase concentrations in blood. From these findings, CS and PLE coatings for cationic lipoplex might produce safe systemic vectors, although they did not increase gene expression in tumor.
  Journal of Drug Targeting 04/2013;
• Article: Hyperbranched dendritic nano-carriers for topical delivery of dithranol.

  Udita Agrawal, Neelesh Kumar Mehra, Umesh Gupta, N K Jain
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  ABSTRACT: Abstract The purpose of the current investigation was to explore the potential of polypropylene imine (PPI) dendrimers to deliver dithranol (DIT) topically and to evaluate its encapsulation, permeation and skin irritation potential. PPI (5.0 generation, 5.0 G) dendrimers and DIT-loaded PPI (DIT-PPI) were prepared and characterized by spectroscopy and transmission electron microscopy. DIT encapsulation, in vitro skin permeation study, skin irritation studies, fluorescent studies and tape stripping studies were performed. Loading of DIT was found to be pH dependent with maximum encapsulation at acidic pH (1.0 ± 0.02, 17.2 ± 0.56 and 57.1 ± 1.32% at 7.4, 5.5 and 1.2 pH, respectively). DIT-PPI showed significantly enhanced permeation rate constant and lesser skin irritation (11.61 ± 1.80 μg/cm(2)/h and 1.0, respectively) when compared with the plain DIT solution (2.72 ± 0.31 μg/cm(2)/h and 2.3, respectively). Skin separation studies and confocal laser scanning microscope images showed that the dye-loaded dendrimers exhibits deposition of dye in pilosebaceous compartment. These studies demonstrate that PPI can be exploited to improve the topical bioavailability of the molecules in a controlled pattern. The enhanced accumulation of DIT via dendrimer carrier within the skin might help optimize targeting of this drug to the epidermal and dermal sites, thus creating new opportunities for well-controlled, modern topical application of DIT for the treatment of psoriasis.
  Journal of Drug Targeting 04/2013;
• Article: Design and evaluation of polyamidoamine dendrimer conjugate with PEG, α-cyclodextrin and lactose as a novel hepatocyte-selective gene carrier in vitro and in vivo.

  Yuya Hayashi, Taishi Higashi, Keiichi Motoyama, Yoshimasa Mori, Hirofumi Jono, Yukio Ando, Hidetoshi Arima
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  ABSTRACT: Abstract To develop a novel hepatocyte-selective gene carrier, we prepared polyamidoamine starburst dendrimer (generation 3, G3) conjugates with three functional molecules, i.e. α-cyclodextrin, polyethylene glycol (PEG, molecular weight = 2170) and lactose (PEG-LαCs), and evaluated gene delivery efficiency of these conjugates in vitro and in vivo. PEG-LαC (G3, degrees of substitution of the PEG moiety (DSP) 2.1) showed higher gene transfer activity than other PEG-LαCs (G3, DSP4.0, 6.2) in HepG2 cells, expressing asialoglycoprotein receptor, and the activity decreased in HeLa cells, non-expressing the receptor and in the presence of asialofetuin. High gene transfer activity of PEG-LαC (G3, DSP2.1) was retained even in the presence of 50% serum, although the activity of α-cyclodextrin/lactosylated dendrimer (G3) conjugate (Lac-α-CDE (G3)), which is lacking a PEG moiety, was severely decreased in the presence of 20% serum. PEG-LαC (G3, DSP2.1) provided negligible cytotoxicity up to a charge ratio of 50 (carrier/pDNA) in HepG2 cells and less acute organ toxicity. PEG-LαC (G3, DSP2.1) showed selective gene transfer activity to hepatic parenchymal cells rather than hepatic non-parenchymal cells. These results suggest that PEG-LαC (G3, DSP2.1) is useful as a hepatocyte-selective gene carrier in vitro and in vivo.
  Journal of Drug Targeting 04/2013;
• Article: Gemcitabine-loaded smart carbon nanotubes for effective targeting to cancer cells.

  Ravendra Singh, Neelesh Kumar Mehra, Vikas Jain, Narendra Kumar Jain
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  ABSTRACT: Abstract Carbon nanotubes (CNTs) are the three-dimensional sp(2) hybridized nano-containers that have attracted considerable interest in drug delivery by offering potential advantages such as biocompatibility, non-immunogenicity, high loading efficiency, intrinsic stability and low toxicities. The aim of the present investigation was to assess the potential of gemcitabine-loaded folic acid (FA) conjugated multi-walled CNTs (GEM/FA-NT) for targeting to breast cancer cells. Pristine MWCNTs was functionalized by FA followed by carboxylation, acylation and amidation and characterized by electron microscopy, FT-IR spectroscopy, X-ray diffraction, entrapment efficiency, cytotoxicity and in vivo studies. FDA-approved GEM was loaded to the purified (GEM-NT) and GEM/FA-NT, and % entrapment efficiency was found to be approximately 71.60 ± 0.25 and 79.60 ± 0.45, respectively. The developed formulation GEM/FA-NT was found to have significantly less hemolytic toxicity (8.23 ± 0.65) as compared to free GEM (17.34 ± 0.56). The in vitro release was found to be in sustained pattern at the lysosomal pH, which depicts more cytotoxic response on human breast cancer cell line (MCF-7). It may be interpreted that the GEM/FA-NT formulation is capable to carry drug and deliver it selectively at the tumor site while minimizing side effects and thus holds promise in chemotherapy.
  Journal of Drug Targeting 03/2013;
• Article: Role of glucose transporters in the intestinal absorption of gastrodin, a highly water-soluble drug with good oral bioavailability.

  Zheng Cai, Juan Huang, Hui Luo, Xiaolu Lei, Zhaoxiang Yang, Yang Mai, Zhongqiu Liu
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  ABSTRACT: Abstract Gastrodin, a sedative drug, is a highly water-soluble phenolic glucoside with poor liposolubility but exhibits good oral bioavailability. The current study aims to investigate whether glucose transporters (GLTs) are involved in the intestinal absorption of gastrodin. The intestinal absorption kinetics of gastrodin was determined using the rat everted gut sac model, the Caco-2 cell culture model and the perfused rat intestinal model. In vivo pharmacokinetic studies using diabetic rats with high GLT expression were performed. Saturable intestinal absorption of gastrodin was observed in rat everted gut sacs. The apparent permeability (Papp) of gastrodin from the apical (A) to basolateral (B) side in Caco-2 cells was two-fold higher than that from B to A. Glucose or phlorizin, a sodium-dependent GLT (SGLT) inhibitor, reduced the absorption rates of gastrodin from perfused rat intestines. In vivo pharmacokinetic studies showed that the time of maximum plasma gastrodin concentration (Tmax) was prolonged from 28 to 72 min when orally co-administered with four times higher dose of glucose. However, the Tmax of gastrodin in diabetic rats was significantly lowered to 20 min because of the high intestinal SGLT1 level. In conclusion, our findings indicate that SGLT1 can facilitate the intestinal absorption of gastrodin.
  Journal of Drug Targeting 03/2013;
• Article: Enhanced bioavailability of orally administered antisense oligonucleotide to nuclear factor kappa B mRNA after microencapsulation with albumin.

  Mohammad Nasir Uddin, Neil J Patel, Tuhin Bhowmik, Bernadette D'Souza, Archana Akalkotkar, Frank Etzlar, Carl William Oettinger, Martin D'Souza
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  ABSTRACT: Abstract Antisense molecules that pertain to ribonucleic acid (RNA) and complementary to the messenger RNA (mRNA) are produced by transcription of a given gene. Antisense oligonucleotides have emerged as potential gene-specific therapeutic agents that are currently undergoing evaluation in clinical trials for a variety of diseases. When administered orally, antisense oligionucleotides have poor bioavailability as they are rapidly degraded by the acid in the stomach and by the enzymes in the intestine. Therefore, the enhancement of bioavailability after oral administration is highly desirable. This article shows the enhanced bioavailability of antisense oligonucleotides that targets nuclear factor kappa B (NF-κB) mRNA after encapsulating in an inert, biodegradable albumin polymer matrix that was administered via the oral route into a rat model. The bioavailability of the antisense oligonucleotides to NF-κB in microencapsulated form was compared to the solution form of the drug upon oral administration. The solution form had a low bioavailability of 9%, whereas the bioavailability for the microencapsulated form of the drug increased up to 70%. Moreover, the other pharmacokinetic parameters including half-life (t1/2) and volume of distribution (Vd) increased for the microencapsulated form compared to the solution form of the drug.
  Journal of Drug Targeting 03/2013;
• Article: Killed Bacillus subtilis spores expressing streptavidin: a novel carrier of drugs to target cancer cells.

  Van Anh Thi Nguyen, Hong Anh Huynh, Tong Van Hoang, Ngoc Thi Ninh, An Thi Hong Pham, Hoa Anh Nguyen, Tuan-Nghia Phan, Simon M Cutting
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  ABSTRACT: Abstract Carriers of drugs in cancer therapy are required to reduce side-effects of the drugs to normal cells. Here we constructed killed recombinant Bacillus subtilis spores (SA1) that expressed streptavidin as a chimeric fusion to the spore coat protein CotB and used the spores as bioparticle carrier. When bound with biotinylated cetuximab these spores could specifically target to the epidermal growth factor receptor on HT 29 colon cancer cells, thereby delivered paclitaxel to the cells with 4-fold higher efficiency, as indicated by fluorescent intensity of paclitaxel Oregon Green 488 bound to HT29 cells. Based on real-time monitoring of cell index, the IC50 of growth of HT29 cells by paclitaxel-SA1-cetuximab was estimated to be 2.9 nM approximately 5-fold lower than water-soluble paclitaxel (14.5 nM). Instability of DNA content was observed when cells were treated with 16 nM paclitaxel-SA1-cetuximab, resulting in a 2-fold enhancement in polyploidy cells. Thus, by targeting the release of paclitaxel to HT29 cells, spore-associated cetuximab augmented the inhibitory effect of paclitaxel on cell division and proliferation. The SA1 could be used as a "universal" drug carrier to target specific biomarkers on cancer cells by conjugating with suitable biotinylated antibodies.
  Journal of Drug Targeting 03/2013;
• Article: DNA-loaded chitosan oligosaccharide nanoparticles with enhanced permeability across Calu-3 cells.

  Yiqing Ye, Yingying Xu, Wanling Liang, George P H Leung, King-Ho Cheung, Caihong Zheng, Fengying Chen, Jenny K W Lam
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  ABSTRACT: Abstract Chitosan oligosaccharide (oligoCS) is a low molecular weight chitosan and its potential for DNA delivery is described here. DNA-loaded oligoCS nanoparticles were prepared by ionic gelation using thiamine pyrophosphate (TPP) as cross-linker. The nanoparticles with oligoCS:DNA: TPP weight ratio of 50:1:25 were approximately 170 nm in diameter with a zeta potential of +40 mV, and were used in the permeability study. The cytotoxicity of oligoCS solutions and nanoparticles was evaluated by MTT assay. The concentrations that exhibited minimal cytotoxicity were employed to investigate their effect on trans-epithelial electrical resistance (TEER) and cellular uptake across the Calu-3 cell layer which was used as a nasal epithelial model. OligoCS nanoparticles were able to cause a significant and reversible decrease in TEER and promote efficient cellular uptake. In addition, the oligoCS nanoparticles were able to enhance paracellular permeability to a greater extent than oligoCS solutions at an equivalent concentration. However, the oligoCS nanoparticles were too large to cross the cell layers through the paracellular route. The transcellular pathway appeared to be the major mechanism of the transportation of oligoCS nanoparticles across the cell layers. OligoCS nanoparticles also allowed efficient DNA incorporation, thereby providing the possibility of controlled nucleic acids release and absorption across epithelial surface.
  Journal of Drug Targeting 03/2013;
• Article: Comparison of PLGA and lecithin/chitosan nanoparticles for dermal targeting of betamethasone valerate.

  Ipek Ozcan, Erkan Azizoğlu, Taner Senyiğit, Mine Ozyazıcı, Ozgen Ozer
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  ABSTRACT: Abstract Poly(lactide-co-glycolide) (PLGA) and lecithin/chitosan (LC) nanoparticles were prepared to evaluate the difference in the behavior upon administration on skin, for steroidal treatment. For this purpose, betamethasone-17-valerate (BMV)-loaded nanoparticles with a narrow size distribution and high entrapment efficiency were prepared. Permeation studies showed that both polymeric nanoparticles enhanced the amount of BMV in epidermis, which is the target site of topical steroidal treatment, when compared with commercial formulation. 1.58-Fold increase was determined in the epidermis concentration of BMV by LC nanoparticles with respect to PLGA nanoparticles. Nanoparticles were diluted in chitosan gel (10%, w/w) to prepare suitable formulation for topical application. Accumulation from both gel formulations were found significantly higher than commercial formulation in skin layers (p < 0.05). In addition, pharmacodynamic responses were also investigated as anti-inflammatory and skin-blanching parameters. Both formulations significantly improved these parameters although they contained 10 times less amount of BMV than commercial cream. Moreover, TEWL measurement exhibited no barrier function changes upon the application of nanoparticles on skin. Overall, both nanoparticles improved the localization of BMV within skin layers; but when compared with PLGA nanoparticles, the LC nanoparticles could be classified as a better candidate for topical delivery vehicle in the treatment of various dermatological inflammatory diseases.
  Journal of Drug Targeting 02/2013;