Journal of Drug Targeting (J DRUG TARGET)

Publications in this journal

• Article: Preparation, characterization, in vivo and biochemical evaluation of brain targeted Piperine solid lipid nanoparticles in an experimentally induced Alzheimer’s disease model Mohammad Yusuf, Maria Khan, Riaz A. Khan, Bahar Ahmed

  Mohammad Yusuf, Maria Khan, Riaz A. Khan, Bahar Ahmed
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  ABSTRACT: Background: Alzheimer is a fast growing disease with imprecise chemical treatments. Increased oxidative stress, decrease in acetylcholine concentration, and appearance of amyloidal proteins are reported in pathology of Alzheimer. Chemical drugs are effective but on the cost of detrimental side effects. Purpose: Present research is based on Preparation, characterization, behavioral and biochemical evaluation of brain targeted Piperine solid lipid nanoparticles in an experimentally induced Alzheimer’s model at a low dose of 2 mg/kg. Methods: Piperine solid lipid nanoparticles were prepared by Emulsification-Solvent Diffusion technique with polysorbate-80 coating to impart Brain specific targeting. Experimental Ibotenic acid induced Alzheimer’s, Force swimming test, superoxide dismutase, acetylcholenesterase enzymatic assays and also Histopathology of brain cortex was conducted to evaluate the Piperine therapeutic effects in Alzheimer’s Disease. Results: Piperine in solid lipid nanoformulation (2 mg/kg equivalent) reduced the SOD values by 504 ± 44.24 m units, p < 0.05, increased the acetylcholenesterase values by 29.24 ± 4.29 µg/mg, p < 0.01 and reduced immobility to 41.36 ± 3.53 s, p < 0.001 and has shown superior results than Donepezil (5 mg/kg). Histopathology studies revealed the reduced plaques and tangles. Conclusions: P-80-PIP-SLN has shown therapeutic effects in Alzheimer via reducing the oxidative stress and reducing the cholinergic degradation at 2 mg/kg dose equivalent. Read More: http://informahealthcare.com/doi/abs/10.3109/1061186X.2012.747529#.UMhoqyIAFy4.facebook
  Journal of Drug Targeting 12/2012;
• Article: Biodistribution characteristics of mannosylated and fucosylated O/W emulsions in mice.

  Wassana Yeeprae, Shigeru Kawakami, Yuriko Higuchi, Fumiyoshi Yamashita, Mitsuru Hashida
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  ABSTRACT: Cell-specific drug delivery is one of the most promising strategies for improving therapeutic efficiency and minimizing systemic toxicity. Carrier systems devoted to receptor-mediated targeting need to be developed. In the case of liver-non-parenchymal cell-specific targeting systems, glycosylated emulsions have been developed as carriers for lipophilic drugs and/or peptides. This present study demonstrates the in vivo disposition behaviour and pharmacokinetic characteristics of mannosylated (Man-) and fucosylated (Fuc-) emulsions incorporated with cholesten-5-yloxy-N-(4-((1-imino-2-D-thiomannosylethyl)amino)alkyl)formamide (Man-C4-Chol) and its fucosylated derivatives (Fuc-C4-Chol), respectively. Man- (or Fuc-) emulsions are composed of soybean oil, EggPC and Man-C4-Chol (or Fuc-C4-Chol) in a weight ratio of 70:25:5. After intravenous administration to mice, these two types of [(3)H]cholesteryl hexadecyl ether (CHE)-labelled glycosylated emulsions were rapidly eliminated from the blood circulation and preferentially recovered in the liver. In contrast, bare (Bare-) emulsions composed of soybean oil:EggPC:cholesterol (Chol) in a weight ratio of 70:25:5 were more retained in the blood circulation. The hepatic uptake clearances of Man- and Fuc-emulsions were 3.3- and 4.0-times greater than that of Bare-emulsions. Interestingly, the hepatic uptake clearance of Fuc-emulsions was significantly higher that that of Man-emulsions. The uptake ratios by non-parenchymal cells (NPC) and parenchymal cells (PC) (NPC/PC ratio) for Bare-, Man- and Fuc-emulsions were found to be 0.4, 2.0 and 2.9, respectively. The hepatic uptakes of [(3)H]CHE-labelled Man- and Fuc-emulsions were reduced by pre-dosing with glycosylated proteins and liposomes. These results clearly support the conclusion that Man- and Fuc-emulsions are promising carrier systems for liver NPC-specific targeting via receptor-mediated mechanism.
  Journal of Drug Targeting 10/2008; 13(8-9):479-87.
• Article: Capture of magnetic carriers within large arteries using external magnetic fields.

  Haitao Chen, Michael D Kaminski, Peter Pytel, Loch Macdonald, Axel J Rosengart
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  ABSTRACT: Our overall research goal is to advance the safety and effectiveness of acute ischemic stroke therapy by improving the benefit/risk ratio of thrombolysis and hence, the long-term outcome of acute ischemic stroke victims. Our approach is the development of a novel tissue plasminogen activator (t-PA) delivery system based on t-PA-loaded magnetic nano- and microcarriers guided directly to the site of vascular occlusion by external magnetic fields. Such a t-PA delivery system would conveniently combine the advantages of both intravenous (systemic) and intraarterial (catheter-facilitated) thrombolysis: non-invasiveness - the magnetic t-PA carriers can be injected intravenously and targeted, as drug delivery is magnetically guided to and t-PA focally released at and within the vascular clot to induce lysis. The focus of our discussion are the two necessary, fundamental and interrelated bioengineering steps: the research and development of well-characterized, biocompatible, functionally active and t-PA-loaded (encapsulated) magnetic nano- and microcarriers able to induce effective thrombolysis, and the design of magnetic guidance systems for targeted tPA-delivery allowing also the triggered release of the thrombolytic agent at the clot site. In this paper, we theoretically demonstrated magnetic trapping of blood borne magnetic nano- and microcarriers from human large vessels, especially arteries. Then, some preliminary experiments using primate models (monkeys) were done to identify successful in vivo sequestration of magnetic carriers in large and smaller arterial branches after arterial upstream and systemic venous injection. Histology (hematoxylin-eosin stain) verified intraarterial carrier concentration (identified as black carrier agglomerates on H and E staining) at the arterial region above the surface magnet. The results revealed the feasibility of magnetic drug-targeting at arteries and solidified the proposed t-PA delivery system.
  Journal of Drug Targeting 06/2008; 16(4):262-8.
• Article: The release and analgesic activities of morphine and its ester prodrug, morphine propionate, formulated by water-in-oil nanoemulsions.

  Jhi-Joung Wang, Chi-Feng Hung, Chi-Hui Yeh, Jia-You Fang
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  ABSTRACT: In this study, we examined the feasibility of water-in-oil (w/o) nanoemulsions as sustained-release systems for morphine, following subcutaneous administration in rats. The ester prodrug of morphine, morphine propionate (MPR), was also utilized in this study. A variety of nanoemulsions were prepared using soybean oil or sesame oil as the external phase. Span 80, Tween 80, Plurol diisostearique and Brij 98 were used as surfactants in the w/o interface. The effects of the formulation variables on the characteristics of the nanoemulsions, such as inner droplet size, zeta potential, viscosity, drug partitioning, drug release and pharmacological effect, were evaluated. Mean sizes of nanoemulsions of 50-200 nm were obtained. The initial surface charge of the emulsions was found to be around - 3 to - 4 mV, except that the Plurol-containing vehicle showed a highly negative charge of - 23 mV. The loading of morphine and MPR into the nanoemulsions resulted in slower sustained-release behavior as compared with the drug/prodrug in aqueous solution. The rate of morphine released across the membrane was found to be highly dependent on the choice of oil and surfactant types. On the other hand, discrepancies in MPR release rates among the various formulations were minimal. The in vivo analgesic duration of morphine by targeting the drug to central nerve system could be prolonged from 1 to 3 h by incorporating the drug into nanoemulsions using Span 80 or Tween 80 as the surfactant. These results suggest that w/o nanoemulsions are well suited to provide sustained morphine delivery for therapeutic purposes.
  Journal of Drug Targeting 06/2008; 16(4):294-301.
• Article: Chloramphenicol-incorporated poly lactide-co-glycolide (PLGA) nanoparticles: formulation, characterization, technetium-99m labeling and biodistribution studies.

  Kamal Krishna Halder, Bivash Mandal, Mita Chatterjee Debnath, Hriday Bera, Lakshmi Kanto Ghosh, Bijon Kumar Gupta
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  ABSTRACT: Chloramphenicol-loaded (CHL) poly-d,l-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were prepared by emulsification solvent evaporation technique either by using polyvinyl alcohol (PVA) as emulsion stabilizer or polysorbate-80 (PS-80) as surfactant and characterised by transmission electron microscopy, zeta-potential measurements. The NPs were radiolabeled with technetium-99m ((99m)Tc) by stannous reduction method. Labeling conditions were optimised to achieve high-labeling efficiency, in vitro and in vivo (serum) stability. The labeled complexes also showed very low transchelation as determined by DTPA challenge test. Biodistribution studies of (99m)Tc-labeled complexes were performed after intravenous administration in mice. The CHL-loaded PLGA NPs coated with PS-80 exhibited relatively high brain uptake with comparatively low accumulation in bone marrow to that of free drug and CHL-loaded PLGA NPs (PVA, used as emulsion stabilizer) at 24 h post injection time period. This indicates the usefulness of the above delivery system for prolonged use of the antibiotic.
  Journal of Drug Targeting 06/2008; 16(4):311-20.
• Article: PLGA microspheres for the delivery of a novel subunit TB vaccine.

  Daniel J Kirby, Ida Rosenkrands, Else M Agger, Peter Andersen, Allan G A Coombes, Yvonne Perrie
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  ABSTRACT: Biodegradable poly(dl-lactide-co-glycolide) microspheres were prepared using a modified double emulsion solvent evaporation method for the delivery of the subunit tuberculosis vaccine (Ag85B-ESAT-6), a fusion protein of the immunodominant antigens 6-kDa early secretory antigenic target (ESAT-6) and antigen 85B (Ag85B). Addition of the cationic lipid dimethyl dioctadecylammonium bromide (DDA) and the immunostimulatory trehalose 6,6'-dibehenate (TDB), either separately or in combination, was investigated for the effect on particle size and distribution, antigen entrapment efficiency, in vitro release profiles and in vivo performance. Optimised formulation parameters yielded microspheres within the desired sub-10 microm range (1.50 +/- 0.13 microm), whilst exhibiting a high antigen entrapment efficiency (95 +/- 1.2%) and prolonged release profiles. Although the microsphere formulations induced a cell-mediated immune response and raised specific antibodies after immunisation, this was inferior to the levels achieved with liposomes composed of the same adjuvants (DDA-TDB), demonstrating that liposomes are more effective vaccine delivery systems compared with microspheres.
  Journal of Drug Targeting 06/2008; 16(4):282-93.
• Article: Chitosan-mediated orally delivered nucleic acids: a gutful of gene therapy.

  Crispin R Dass, Peter F M Choong
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  ABSTRACT: Gene therapy is rapidly gaining its hold in preclinical drug evaluation. However, upfront, ease of administration and greater patient compliance should strictly drive research efforts for developing modes of gene delivery. It has been a decade since plasmid DNA was first introduced orally in animals. Since then, two main modes of such delivery for potentially therapeutic nucleic acids, chitosan-based systems and non-chitosan-based systems, have been developed, at a steady though slow pace. This slow pace is partly due to the various hurdles faced with oral delivery, especially for labile molecules like nucleic acids. The real challenge is to enhance delivery systems that can traverse the gut and gain entry into the bloodstream in sufficient quantities for efficacy in diseased tissues at a distance. This review examines some of the current chitosan-based vehicles used for oral administration of potentially therapeutic nucleic acids, and explores novel ways to better deliver such molecules in the future for non-vaccination applications.
  Journal of Drug Targeting 06/2008; 16(4):257-61.
• Article: Enhanced mucosal and systemic immune response with squalane oil-containing multiple emulsions upon intranasal and oral administration in mice.

  Aliasgar Shahiwala, Mansoor M Amiji
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  ABSTRACT: The objective of this study was to develop and evaluate squalane oil-containing water-in-oil-in-water (W/O/W) multiple emulsion for mucosal administration of ovalbumin (OVA) as a model candidate vaccine in BALB/c mice. Control and optimized OVA-containing W/O/W emulsion (OVA-Emul) and chitosan-modified W/O/W emulsion (OVA-Emul-Chi) formulations were administered intranasally and orally at an OVA dose of 100 mug. The mucosal and systemic immune responses were evaluated after the first and second immunization. The OVA-Emul formulations resulted in higher immunoglobulin-G (IgG) and immunoglobulin-A (IgA) responses as compared with aqueous solution. In addition, significant IgG and IgA responses were observed after the second immunization dose using the emulsions with both routes of administration. Intranasal vaccination was more effective in generating the systemic OVA-specific IgG response than the mucosal OVA-specific IgA response. Oral immunizations, on the other hand, showed a much higher systemic IgG and mucosal IgA responses as compared with the nasally treated groups. The results of this study show that squalane oil-containing W/O/W multiple emulsion formulations can significantly enhance the local and systemic immune responses, especially after oral administration, and may be adopted as a better alternative in mucosal delivery of prophylactic and therapeutic vaccines.
  Journal of Drug Targeting 06/2008; 16(4):302-10.
• Article: Efficient in vivo gene transfection by stable DNA/PEI complexes coated by hyaluronic acid.

  Tomoko Ito, Naoko Iida-Tanaka, Yoshiyuki Koyama
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  ABSTRACT: Plasmid DNA was mixed with polyethyleneimine (PEI) and hyaluronic acid (HA) to afford ternary complexes with negative surface charge regardless of the mixing order. They showed reduced non-specific interactions with blood components. When DNA and PEI were mixed at a high concentration such as that used in in vivo experiments, they soon aggregated, and large particles were formed. On the other hand, pre-addition of HA to DNA prior to PEI effectively diminished the aggregation, and 10% (in volume) of the complexes remained as small particles with a diameter below 80 nm. Those negatively charged small ternary complexes induced a much stronger extra-gene expression in tumor than binary DNA/PEI complex after intratumoral or intravenous injection into the mice bearing B16 cells.
  Journal of Drug Targeting 06/2008; 16(4):276-81.
• Article: Folate-targeted etoposide-encapsulated lipid nanospheres.

  Ram Reddy Patlolla, Venkateswarlu Vobalaboina
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  ABSTRACT: Lipid nanospheres (LN) are simple colloidal drug delivery systems, which are proven to be useful for the systemic delivery of lipophilic anticancer drugs. Our previous work shows that the encapsulation of etoposide in LN improved the anticancer activity and a further inclusion of polyethylene glycol-distearoylphosphatidylethanolamine (DSPE-PEG) increased the circulation time and stability of LN. The present study is focused on the targeting ability of LN using Folate-PEG-DSPE. Folate-targeted (Fol-LNE) and non-targeted (SLNE) etoposide-encapsulated lipid nanospheres were prepared with the help of soybean oil, egg phosphatidylcholine, and PEG-DSPE with and without Folate-PEG-DSPE. The anticancer activity of these formulations was assessed in KB cell line. Cell uptake studies were carried out in KB cell lines using fluorescent-labeled targeted (Fol-LN) and non-targeted (SLN) lipid nanospheres without etoposide. Confocal microscopy and flow cytometry results found that, Fol-LN was selectively taken up by the KB cells and the addition of 1 mM folic acid completely blocked this uptake. Cytotoxicity results support the above finding, the IC50 values of etoposide solution, Fol-LNE, and Fol-LNE-comp (competition with 1 mM folic acid) were 33, 5, and 19 muM, respectively. Tissue distribution of Fol-LNE was compared with that of SLNE and etoposide commercial formulation (ETP) in normal mice. The studies show that in the kidney etoposide concentration was higher following Fol-LNE administration than SLNE and ETP.
  Journal of Drug Targeting 06/2008; 16(4):269-75.
• Article: Temporal and spatial control of neural effects following intracerebral microinfusion.

  Jill M Stukel, Jason Parks, Michael R Caplan, Stephen I Helms Tillery
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  ABSTRACT: Spatial and temporal control of neural drug delivery is critical for many therapeutic applications and analyses of brain patterns and behavior. Specifically, for localized injections that serve to deliver drug or inactivate an isolated tissue region in order to observe changes in neural activity at that site, excess distribution into surrounding regions may confound analysis or adversely affect healthy tissue. Here, we develop a mass transport model that simulates a short period of initial infusion of inactivating drug, followed by a successive convective wash with artificial cerebrospinal fluid (aCSF), while tracking the regions of tissue that are above a certain threshold concentration of inactivating agent. We analyze the effect of parameters such as effective diffusion coefficient, extracellular volume fraction, and injectate concentration upon spatiotemporal distribution profiles. Further, we observe the effects of following the initial injection with a wash-out period with aCSF upon the breadth of the volume affected by the injectate. These simulations indicate that, by injecting small volumes of drug at low concentrations and following them with an aCSF flush, a well-delineated region of tissue can be altered for a controlled duration.
  Journal of Drug Targeting 05/2008; 16(3):198-205.
• Article: Percutaneous absorption of interferon-alpha by self-dissolving micropiles.

  Yukako Ito, Atsushi Saeki, Keiji Shiroyama, Nobuyuki Sugioka, Kanji Takada
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  ABSTRACT: To ascertain the pharmaceutical usefulness of self-dissolving micropiles (SDMPs) containing interferon (IFN), two types of SDMPs were prepared using chondroitin sulfate and dextran as the base. After percutaneous administration of 5000 IU/kg IFN-alpha2b SDMP to rats, serum IFN levels were measured for 6 h. The peak serum IFN level, maximum drug concentration (Cmax), and the time when serum IFN level reaches to Cmax, time to reach maximum concentration (Tmax), were 8.2+/-0.5 IU/ml and 1.2+/-0.1 h, respectively, for chondroitin SDMP. For dextran SDMP, Cmax and Tmax were 3.1+/-0.4 IU/ml and 3.3+/-0.3 h, respectively. AUC of chondroitin SDMP was 1.5 times greater than that of dextran SDMP. Bioavailabilities (BAs) of IFN were 378.3% for chondroitin SDMP and 255.9% for dextran SDMP that were larger than 100%. The BA of IFN from subcutaneous (s.c.) injection solution was 320.9%. The relative BAs of IFN SDMPs against s.c. injection solution were 117.8% for chondroitin SDMP and 79.9% dextran SDMP. An in vitro release experiment suggested the faster release rate of IFN from chondroitin SDMP, 57.3% at 5 min, than dextran SDMP, 32.6% at 5 min. Chondroitin SDMP containing IFN showed good stability for 3 months and no damage to the administered rat skin.
  Journal of Drug Targeting 05/2008; 16(3):243-9.
• Article: Novel galactosylated SLN for hepatocyte-selective targeting of floxuridinyl diacetate.

  Jiafang Lian, Sanqi Zhang, Jingwen Wang, Kunquan Fang, Yanmin Zhang, Yong Hao
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  ABSTRACT: This paper describes the preparation and liver-targeting traits of new solid lipid nanoparticles (SLN) containing floxuridinyl diacetate (FUDRA) modified with beta-d-galactosides (Gn). FUDRA and Gn were incorporated, respectively, to study the drug loading (DL), drug release, and in vivo distribution property. Transmission electron microscopy analysis revealed that the particle sizes of FUDRA-SLN, FUDRA-G2SLN and FUDRA-G10SLN were 215.3, 91.3 and 106.0 nm, with DLs of 8.20, 8.37 and 8.91%, respectively. In an in vivo study of Specific pathogen-free mice, the complexes were administered via the tail vein. Judging on the basis of 5-fluoro-2'-deoxyuridinum (FUDR) concentration in blood and viscera with HPLC analysis, FUDRA release was confirmed and a significant enrichment of SLN modified with Gn was observed in the liver with Gn complex (targeting rates of SLN-G2 and SLN-G10 are 11.25 and 11.43 for the liver, respectively) in comparison with FUDR-sol (targeting rate is 1.71). In mice, FUDR could be detected in the liver at 40, 160, 320 and 480 min after i.v. administration of FUDR-sol, FUDRA-SLN, FUDRA-G2SLN and FUDRA-G10SLN, respectively. These results suggest that G2 and G10 are ideal materials for preparing active liver targeting SLN. FUDRA-G2SLN and, particularly, FUDRA-G10SLN have desirable hepatocyte-selective targeting and sustained-release action in healthy mice.
  Journal of Drug Targeting 05/2008; 16(3):250-6.
• Article: Immunostimulatory biodegradable implants containing the adjuvant Quil-A--Part II: In vivo evaluation.

  Julia Myschik, Warren T McBurney, Tania Hennessy, Amanda Phipps-Green, Thomas Rades, Sarah Hook
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  ABSTRACT: Sustained-release formulations have drawn the attention of formulation scientists working in the area of vaccine research because these systems may reduce the need for booster immunisations. This would be of great advantage especially for the administration of subunit vaccines. The aim of this study was to illustrate the performance of liposome-forming, sustained-release lipid implants containing 2% of the adjuvant Quil-A (QA) (w/w of total lipids) and ovalbumin (OVA) as a model antigen, in an in vivo study using C57Bl/6 mice. QA/OVA-containing lipid implants were administered subcutaneously and stimulated a similar magnitude of immune response when compared with an immediate-release formulation that contained an equivalent amount of adjuvant and antigen but was administered twice. The novel implant system presented here combines the advantages of both sustained release and particulate delivery in one formulation.
  Journal of Drug Targeting 05/2008; 16(3):224-32.
• Article: Performance studies of a conical nozzle designed for the macromolecular skin delivery.

  Yi Liu, George Costigan, Brian J Bellhouse
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  ABSTRACT: Human skin is an attractive site for the delivery of protein and peptide-based macromolecular drugs for the treatment of topical and systemic diseases as well as for DNA immunisation. However, the delivery of those macromolecules in or across the skin is undesirably limited due to its permeation property. To expand the number of macromolecules to be delivered to specific targeting tissue/cells, a unique biomedical device, the handheld powdered injection system, has been developed. It is a novel transdermal technology that disposes needles (and syringes), circumvents the need for refrigeration (of vaccines) and has the potential to revolutionise the treatment and prevention of major diseases. To further underwrite device characteristics, in this paper, an advanced computational fluid dynamics technology is utilised to model gas, particle dynamics and gas-particle-target interaction. The statistical analyses show that the microparticles can achieve a mean velocity of 704 m/s representative of intracellular macromolecular deliveries. Knowledge on the gas and particle dynamics can be applied to design effective and efficient handheld powdered delivery systems.
  Journal of Drug Targeting 05/2008; 16(3):206-12.
• Article: Immunostimulatory biodegradable implants containing the adjuvant Quil-A--Part I: Physicochemical characterisation.

  Julia Myschik, Friederike Eberhardt, Thomas Rades, Sarah Hook
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  ABSTRACT: Sustained-release vaccines offer the potential to reduce, or obviate, the need for repeated dosing of vaccines. In this study, we report the development and characterisation of sustained-release lipid implants that release immunogenic, self-assembling colloidal particles. Lipid implants consisting of cholesterol (CHOL), phosphatidylcholine (PC), the adjuvant Quil-A (QA) and the model antigen ovalbumin (OVA) were formulated and investigated using a variety of techniques. Transmission electron microscopy was utilised to demonstrate the release of colloidal structures from these implants over time. The nature of the colloidal particles varied depending on the ratio of QA:CHOL:PC. The release of the model antigen as well as its incorporation into the colloidal particles was investigated using a fluorescent tag covalently coupled to OVA and quantified using fluorospectrophotometry. The antigen release was modified by the incorporation of excess CHOL into the formulation and was not only dependent on the ratio of QA:CHOL:PC but also on the nature of the model antigen. Alteration of the hydrophobicity of the model antigen resulted in an increased incorporation into the colloidal structures. Surface changes of the implants were analysed using scanning electron microscopy. The implant formulations investigated in this study show a potential for the delivery of subunit vaccines.
  Journal of Drug Targeting 05/2008; 16(3):213-23.
• Article: Design and synthesis of novel galactosylated polymers for liposomes as gene drug carriers targeting the hepatic asialoglycoprotein receptor.

  Si Ling Wang, Feng Bo Yu, Tong Ying Jiang, Chang Shan Sun, Tianyi Wang, Jing Hai Zhang
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  ABSTRACT: The 18-mer oligodeoxynucleotides (ODNs) that can inhibit survivin gene expression were selected as a model gene drug to study hepatic-targeting drug delivery system. Novel galactosylated polymers (cholesteryloxycarbonylamino) ethylamine-alpha,beta-polyasparthydrazied (CHE-PAHy-Lacs), which target asialoglycoprotein receptor on hepatic parenchymal cells (PC), were designed and synthesized as non-toxic, non-antigenic and non-teratogenic ligands for liposomes. The liposomes incorporating different CHE-PAHy-Lacs were prepared and characterized by zeta potential and particle size analyzer. The drug encapsulation efficiency was measured by gel filtration method. 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate was used as a marker for all the liposome preparations in the in vivo experiments. The CHE-PAHy-Lac liposomes produced a significant improvement in the encapsulation efficiency of ODNs (28.73-51.37%) compared with conventional liposomes (9.88%). The in vivo results showed that the liposomes incorporating CHE-PAHy-Lac, which contained about 30% (w/w) galactosyl residues, exhibited marked accumulation in the liver and hepatic PC. These results suggest that the novel galactosylated polymers used for liposomes have a great potential as a gene delivery system for hepatic targeting.
  Journal of Drug Targeting 05/2008; 16(3):233-42.
• Article: Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa.

  Mamoru Shoji, Aiming Sun, Walter Kisiel, Yang J Lu, Hyunsuk Shim, Bernard E McCarey, Christopher Nichols, Ernest T Parker, Jan Pohl, Cara A Mosley, Aaron R Alizadeh, Dennis C Liotta, James P Snyder
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  ABSTRACT: Tissue factor (TF) is aberrantly expressed on tumor vascular endothelial cells (VECs) and on cancer cells in many malignant tumors, but not on normal VECs, making it a promising target for cancer therapy. As a transmembrane receptor for coagulation factor VIIa (fVIIa), TF forms a high-affinity complex with its cognate ligand, which is subsequently internalized through receptor-mediated endocytosis. Accordingly, we developed a method for selectively delivering EF24, a potent synthetic curcumin analog, to TF-expressing tumor vasculature and tumors using fVIIa as a drug carrier. EF24 was chemically conjugated to fVIIa through a tripeptide-chloromethyl ketone. After binding to TF-expressing targets by fVIIa, EF24 will be endocytosed along with the drug carrier and will exert its cytotoxicity. Our results showed that the conjugate inhibits vascular endothelial growth factor-induced angiogenesis in a rabbit cornea model and in a Matrigel model in athymic nude mice. The conjugate-induced apoptosis in tumor cells and significantly reduced tumor size in human breast cancer xenografts in athymic nude mice as compared with the unconjugated EF24. By conjugating potent drugs to fVIIa, this targeted drug delivery system has the potential to enhance therapeutic efficacy, while reducing toxic side effects. It may also prove to be useful for treating drug-resistant tumors and micro-metastases in addition to primary tumors.
  Journal of Drug Targeting 05/2008; 16(3):185-97.