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- Volume 11, Issue 5, 2014
Current Drug Delivery - Volume 11, Issue 5, 2014
Volume 11, Issue 5, 2014
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Editorial (Thematic Issue: Unlocking the Potential of Stem Cells in Cell Therapy, Drug Delivery and Drug Discovery)
More LessIn metazoans, adult, tissue-specific stem cells function to naturally replace and regenerate components of organ systems during life. The restorative power of adult stem cells has been best exploited clinically in bone marrow transplantation to treat blood cancers and other disorders. With the discovery and characterisation of other adult stem cell types and pluripotent stem cells capable of generating all tissues in the body, it has been postulated that stem cells may be of utility in replacing other tissues which have stopped functioning due to age or disease. However, the potential application of stem cells to regenerative medicine is vast and more multi-faceted than simply furnishing replacement tissue in failing organ systems. In this minithematic issue of Current Drug Delivery, we explore these other applications focusing on current knowledge about the regulation of stem cells, its implications for pathogenesis in cancer and cell therapy and how stem cells may be used as drug delivery agents and as tools in disease modelling and drug discovery. Adult stem cell function during homeostasis and in response to periods of physiological demand relies on strict intrinsic regulation interwoven with complex extrinsic signals emanating from the micro-environment (or ‘niche’). That proper adult stem cell function in vivo is dependent on its niche was the concept first invoked in the blood system in the 1970s and is an idea that has gained considerable traction in this and other tissue systems more recently. The overall complexity of adult stem cell niches is gradually being understood at the level of cellular constituents and molecular pathways controlling their behaviour. In addition to its purely supportive role as a habitat for the stem cell, it is responsible for secreting growth factors and other regulatory proteins that extrinsically regulate stem cell functionality. Crawford and colleagues review the role of pigment epitheliumderived factor (PEDF), a critical regulator of neural stem cell self-renewal in the neural stem cell niche. The authors explore the potential therapeutic role of PEDF where its opposing positive effect on stem cell behaviour and powerful anti-angiogenic effect on cancers make it possible for it to operate as a selective drug in cancer while sparing or possibly boosting normal tissue function through harnessing endogenous stem cell function. It has also become increasingly clear how crucial the stem cell-niche collaboration is to the maintenance of normal tissue function: in the blood system the potentially dire consequences of disturbing particular constituents of the niche are evident in decreased stem cell function and the emergence of pre-cancerous and cancerous conditions in mouse models and select clinical syndromes. The niche may also provide a sanctuary that protects already existent cancer from the effects of treatment (e.g. chemotherapy), and enables eventual disease relapse. Bartos and Dubielecka-Szczerba explore how one potential component of the niche - actin cytoskeleton- is impacted by the Bcr-abl oncogene in chronic myeloid leukaemia, leading to drug and therapy resistance. Pluripotent stem cells, derived from the embryo (embryonic stem cells) or by reprogramming somatic cells to an embryonic state (induced pluripotent stem cells), and adult stem cells may impact cellular therapy in two distinct ways. As alluded to, they may directly replace damaged tissues in organ transplantation related strategies (see review by Stewart for examples using pluripotent stem cell derived tissue). Less well established but becoming more appreciated is that stem cells can function and act as drug delivery modalities, facilitating tissue replacement without formally integrating or replacing tissue. A case in point is mesenchymal stem/stromal cells (MSCs), which as English and colleagues discuss, have potent immune modulatory function that could be deployed to facilitate acceptance of allogeneic organ transplantation or to ameliorate graft versus host disease, a potentially fatal side-effect of allogeneic bone marrow transplantation (for another example, see Falanga and colleagues review of the use of MSCs to treat chronic wounds). Shinya Yamanaka was awarded the Nobel Prize in Physiology and Medicine in 2012 for discovering induced pluripotent stem cells (iPSCs), underscoring their potential to revolutionise therapies for a plethora of debilitating and fatal diseases via cell replacement therapy or drug discovery. For example, the capacity to make iPSCs from a somatic cell of a patient afflicted with a given disease offers an unprecedented opportunity to peer into the evolution of that disease by essentially rewinding its history in vitro and modelling the earliest pathological steps associated with it, with an ultimate view of identifying drug targets for treatment. Stewart reviews and explains progress made to date with disease specific iPSCs in this context set against a historical perspective of the pluripotent stem cell biology field. Finally, translating the potential of pluripotent stem cell derived tissue or adult stem cells (e.g. MSCs) into both safe and effective clinical therapies in any setting involving administration of cellular products requires adherence to Good Manufacturing Practice (GMP) supervised by the Food and Drug Administration (FDA) regulatory framework in the United States and by the European Medicines Agency (EMA) in Europe. Falanga and colleagues outline the laborious yet essential strategy required to establish a GMP lab for these purposes and describe their experience with using the laboratory to manipulate MSCs that will encourage chronic wound healing.
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PEDF & Stem Cells: Niche vs. Nurture
Authors: Philip Fitchev, Chuhan Chung, Beth A. Plunkett, Charles B. Brendler and Susan E. CrawfordAnti-angiogenic pigment epithelium-derived factor (PEDF) is a multifunctional 50kD secreted glycoprotein emerging as a key factor in stem cell renewal. Characteristics of the stem cell niche can be highly dependent on location, access to the vasculature, oxygen tension and neighboring cells. In the neural stem cell (NSC) niche, specifically the subventricular zone, PEDF actively participates in the self renewal process and promotes stemness by upregulating Notch signaling effectors Hes1 and Hes5. The local vascular endothelial cells and ependymal cells are the likely sources of PEDF for the NSC while mesenchymal and retinal stem cells can actually produce PEDF. The opposing actions of PEDF and VEGF on various cells are recapitulated in the NSC niche. Intraventricular injection of PEDF promotes stem cell renewal, while injection of VEGF prompts differentiation and neurogenesis in the subventricular zone. Enhancing the expression of PEDF in stem cells has promising therapeutic implications. Bone marrow mesenchymal stem cells overexpressing PEDF effectively inhibited pathologic angiogenesis in the murine eye and these same cells suppressed hepatocellular carcinoma growth. As a protein with bioactivities in nearly all normal organ systems, it is likely that PEDF will continue to gain visibility as an essential component in the development and delivery of novel stem cell-based therapies to combat disease.
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Mesenchymal Stromal Cells; Role in Tissue Repair, Drug Discovery and Immune Modulation
Authors: Karen English, Bernard P. Mahon and Kathryn J. WoodMesenchymal stromal cells (MSCs) participate in repair of damaged tissues, possess the potential to serve as a useful tool in the drug discovery field and exert immunosuppressive effects as demonstrated by their ability to modulate the immune response. Herein, the roles played by MSC differentiation and/or production of trophic factors involved in tissue repair are discussed. MSCs offer the opportunity to probe targets that conventional or differentiated cell lines do not express; thus providing a more refined system that allows identification of novel therapeutics. However, there are difficulties associated with drug discovery assays to which MSCs are not exempt. The immunosuppressive potential of MSCs has already been utilised in clinical trials where MSCs have been used to treat patients with graft- versus- host disease (GvHD) and autoimmune diseases. Another possible therapeutic application of MSCs lies in the field of transplantation tolerance. Although the capacity of MSCs to modulate immune responses has received much attention, the role of MSCs in transplantation tolerance is as yet unclear. In this review, we discuss the evidence for MSC induction of a state of tolerance in the transplantation setting.
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Topical Delivery of Cultured Stem Cells to Human Non-Healing Wounds: GMP Facility Development in an Academic Setting and FDA Requirements for an IND and Human Testing
Authors: Tatyana Yufit, Polly Carson and Vincent FalangaWith increasing emphasis on translational research, the need for appropriate regulatory oversight and approval has become essential. The requirements of the Food and Drug Administration (FDA) for Investigational New Drug (IND) exemption in studies that are investigator-initiated have become increasingly stringent. Moreover, academic institutions have not had substantial experience in establishing Good Manufacturing Practice (GMP) facilities required for manipulating human cells in vitro and for chemical or biochemical manufacturing. GMP regulations are established by the FDA under the authority of the Federal Food, Drug and Cosmetic Act. In this report, the authors outline the general strategy and some critical steps that an investigator and the institution may find helpful in developing a GMP facility, especially in an academic center. Also, more specifically and as proof of principle, we describe our approach to culturing autologous bone marrow-derived human mesenchymal stem cells (MSCs) and delivering them to non healing wounds. The lessons learned in this often lengthy and challenging process may be helpful to other academic institutions and investigators embarking on manipulating and delivering viable cells for human experimentation.
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The Emerging Role of Bcr-Abl-Induced Cystoskeletal Remodeling in Systemic Persistence of Leukemic Stem Cells
Authors: Adrian Bartos and Patrycja M. DubieleckaAbl kinase plays a critical role in development and homeostasis of hematopoietic system. The importance of this kinase becomes apparent from the consequences of a specific, reciprocal translocation between chromosome 9 and chromosome 22 that yields a chimeric fusion protein, Bcr-Abl, in which the function of auto-regulatory mechanisms are inactivated. The resultant constitutively active kinase is responsible for development of a systemic leukemogenic phenotype. Studies employing currently available highly specific inhibitors, with high potency to block kinase activity, uncovered unanticipated characteristics of Bcr-Abl fusion protein. It became apparent that the kinase domain, with its primary significance for development and progression of leukemia, is not solely responsible for leukemogenic features of the Bcr-Abl transformed leukemic stem cells. In this review we summarize current understanding of non-enzymatic characteristics of Bcr-Abl, its effect on actin cytoskeleton, and its potential contribution to drug resistance and systemic persistence of leukemic stem cells.
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Pluripotency and Targeted Reprogramming: Strategies, Disease Modeling and Drug Screening
More LessPluripotent stem cell research has developed over the last fifty years from the study of embryonic development to a multifaceted discipline that encompasses development, epigenetics, reprogramming, cell therapy, disease modeling and chemical and drug screening. The idea of patient-specific therapies and disease modeling using human pluripotent stem cells has been the theoretical golden-egg of the field since the generation of human embryonic stem cells. With the advent of induced pluripotent stem cells (PSCs), the ability to generate patient-specific cells for therapeutic use, to model disease progression and to test drugs on disease relevant cells moved a large step closer to reality. While there still is a long way to go before the results of PSC research is found in the clinic or in the pharmacy, recent developments have demonstrated that it is possible to generate patient-specific pluripotent cells which can differentiate into disease relevant cell types, are amenable to gene correction, can phenocopy molecular and functional disease characteristics, at least in vitro, and can be used to validate the efficacy of therapeutic compounds. This review will cover recent developments in the generation and manipulation of pluripotent stem cells with a focus on the use of pluripotent stem cells for disease modeling and therapeutic drug screening. In addition, the latest developments in somatic cell reprogramming will also be discussed.
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Temporal Separation in the Release of Bioactive Molecules from a Moldable Calcium Sulfate Bone Graft Substitute
Authors: Matt E. Brown, Yuan Zou, R. Peyyala, Thomas D. Dziubla and David A. PuleoTreatment of infected bone defects presents a considerable challenge due to the complications that occur from significant bone damage concomitant with contaminated tissue. These wounds are most often treated in a two-step sequence, where the infection is first eliminated before any attempt to repair the bone is undertaken. In order to combine these two treatment steps into one procedure, a moldable bone grafting material was developed to deliver drugs in a temporally separated manner. This was accomplished by a two-layered calcium sulfate composite consisting of a moldable outer shell containing antibiotic-loaded poly(lactic-co-glycolic acid) microspheres wrapped around a preformed core containing an osteogenic drug. The release of vancomycin from the shell portion began immediately and continued over the course of 6 weeks, while the release of simvastatin from the core was delayed for 12 days before being released over the next 4 weeks. Bioactivity of vancomycin was shown in modified Kirby-Bauer experiments in which whole samples inhibited Staphylococcus aureus (S. aureus) growth for 2 weeks. This two-layered system is capable of delivering antibiotics locally for clinically relevant periods of time and delaying the release of osteogenic drugs to mimic a two-step procedure that has potential for treating infected bone defects.
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Designing and In-Vitro Characterization of Micelle Forming Amphiphilic PEGylated Rapamycin Nanocarriers for the Treatment of Gastric Cancer
More LessThe present study aims to develop and explore the use of PEGylated rapamycin (RP-MPEG) micelles for the treatment of gastric cancer. RP-MPEG was synthesized and characterized by using IR, H1 NMR and C13 NMR. RP-MPEG was prepared in the form of micelles and characterized by using field emission scanning electron microscopy, dynamic light scattering, zeta sizer, chromatographic analyses and photostability studies. The cytotoxicity studies of RP-MPEG micelles were conducted on specific CRL 1739 human gastric adenocarcinoma and CRL 1658 NIH-3T3 mouse embryonic fibroblast cell lines. RP-MPEG micelles showed the particle size distribution of 125±0.26 nm with narrow size distribution (polydispersity index 0.127±0.01). The surface charge of RP-MPEG micelles was found to be -12.3 mV showing enhanced anticancer activity against the CRL 1739 human gastric adenocarcinoma cell lines with an IC50 value of 1 mcg/ml.
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Three Levels Face Centered Central Composite Design of Colon Targeted Micro-Particulates System of Celecoxib: Screening of Formulations Variables and in vivo Studies
Authors: Bankim Chandra Nandy, Vinod Verma, Sanjay Dey and Bhaskar MazumderCelecoxib is a well known non-steroidal anti-inflammatory drug (NSAID) and extensively employed for the treatment of arthritis. The aim of the present study was to design, develop and optimization of micro particulates system, for colon specific delivery of celecoxib for both local (in prophylaxis of colorectal adreno-carcinoma) and systemic (in chrono-therapeutic treatment of arthritis) therapy. The aim of the present work was to elucidate the effect of formulation variables e.g., amount of eudragit polymer (X1), surfactant concentration (X2) and agitation speed (X3) on in-vitro release profiles (Y1-Y3), drug entrapment efficiency (Y4) and particle size (Y5) of micro-particulates system of celecoxib. Microspheres were formulated with the combination of ethyl cellulose (EC) and eudragit RS100/eudragit S100; by using a novel quasi emulsion solvent diffusion technique. Developed formulations were characterized and evaluated on the basis of FTIR, thermal, particle size, SEM and XRD analysis. The formulation variables were optimized by response surface methodology (RSM). Best optimized delayed release formulation was further subjected to the in vivo x-ray studies to evaluate the site specificity. It was found that in-vitro release (Y1-Y3) decreased significantly (p<0.05) with increase in amount of eudragit polymer but increased significantly (p<0.05) with an increase in surfactant concentration and stirring speed. FTIR study indicated that no strong chemical interaction took place between the drug and excipients of prepared formulations. DSC and XRD studies indicated that drug was present in the amorphous state. The X-ray photographs revealed that the swelling layer eroded from the outer surface and a size reduction was seen after 6 hrs when optimized microspheres reached the site of colon. Therefore, this approach suggested that the combination of eudragit S100 and ethyl cellulose microspheres may be useful for the delivery of maximum amount of celecoxib in intact form to the colon.
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Preparation and in-vitro Transfection Efficiency Evaluation of Modified Cationic Liposome-polyethyleneimine-plasmid Nanocomplexes as a Novel Gene Carrier
Authors: Asma Mahmoudi, Reza Kazemi Oskuee, Mohammad Ramezani and Bizhan Malaekeh-NikoueLiposome-linear polyethyleneimine (PEI)-DNA nanocomplexes have shown to be effective non-viral gene delivery vectors. In the present study, we tried to improve the transfection efficiency of these nanocomplexes by liposome modification. For this purpose, the lipopolymer was prepared by the conjugation of hexylacrylate to the PEI. Liposomes comprising lipopolymer and DOTAP (1.2-DiOleoyl-3-Trimethyl Ammonium-Propane) were prepared and extruded through polycarbonate filters to obtain the desired size. The 2.5, 25 and 250 KDa molecular weights of linear PEI have been used in order to prepare modified liposome-PEI-DNA nanocomplexes. Three C/P ratios of each nancomplex were premixed. Size, zeta potential and the DNA condensation ability of these complexes were determined separately, and in the end, the transfection efficiency and cell cytotoxicity of prepared vectors were evaluated on Neuro2A cell line. Mean particle size of all of these nanocomplexes was lower than 220 nm with surface charge of 17.5 to 25.9 mV. The lipopolyplexes (comprising modified liposome:PEI:DNA), modified liposome (as lipoplex) and PEI 250KDa (as polyplex) showed the highest transfection efficacy. This activity was amplified by increase carrier to plasmid (C/P) ratio. In addition, the metabolic activity of prepared vectors was 80-100% for control group. In conclusion, the prepared lipopolyplexes showed high ability to enhance gene transfer.
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Effect of Combination of Acrylic Polymers on the Release of Nevirapine Formulated as Extended Release Matrix Pellets Using Extrusion and Spheronization Technique
Authors: Anshuli Sharma, Anjaneya Prasad, Kamal Dua and Gurvinder SinghThe aim of the present research work was to formulate and evaluate the extended release matrix pellets of nevirapine using extrusion and spheronization technique which will be an alternative technique for making extended release dosage forms and to compare the drug release profiles of the formulations with the reference product. In vitro dissolutions were carried out in 0.04M Phosphate buffer pH 6.8 with 2% w/v SLS (sodium lauryl sulphate) for 24 hours with USP type I apparatus at 75rpm. The drug release from the optimised formulation was comparable to that of the reference product and follows first order kinetics followed by non-fickian transport mechanism of drug release which confirms the drug release pattern involves complex mixture of diffusion and erosion. The similarity factor, f2 value of optimised formulation was found to be 70, which shows that the developed formulation was comparable to that of the reference product.
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Influence of Gold Nanoparticle Tagged Snake Venom Protein Toxin NKCT1 on Ehrlich Ascites Carcinoma (EAC) and EAC Induced Solid Tumor Bearing Male Albino Mice
Authors: Tanmoy Bhowmik, Partha Pratim Saha, Anjan Kumar DasGupta and Antony GomesEarlier the conjugation of gold nanoparticle (GNP) and snake venom protein toxin NKCT1 was reported and primary characterization was performed. In the present communication, further characterizations of GNP-NKCT1 were done with SEM, EDS, XRD and Raman spectra for its physio-chemical nature and bonding. SEM showed the formation of gold nanoparticles, whereas EDS and XRD confirmed 60-90% gold nanoparticles in the solution. Raman shift corresponding to (C=O), (N-H), (C-N) confirmed the proper conjugation of GNP with NKCT1. GNP-NKCT1 showed anticancer effect both in vivo and in vitro in EAC cell and antitumor effect in EAC induced mice. In in vivo studies, GNPNKCT1 increased MST 108.30% and decreased viable EAC cell count 51.39%. Fluorescent micrograph showed signs of apoptosis (membrane blebbing, membrane disruption). Decreased level of IL-10 and low incorporation of BrdU showed decreased proliferation of EAC induced by GNP-NKCT1. With upregulation of Bax, down regulation of Bcl2 and increased expression of caspase 3/9, it was confirmed that GNP-NKCT1 induced caspase dependent apoptosis pathway in EAC cell. In in vitro studies, GNP-NKCT1 increased the late apoptotic stage of cell and arrested cell cycle division at G0/G1 state. GNP-NKCT1 also decreased the tumor volume and tumor weight in EAC induced tumor in male albino mice. It inhibited angiogenesis, which was confirmed by lower percentage of expression of VEGF. This study indicated the capability of gold nanoparticles which enhanced the tumor uptake of NKCT1 and also suggested that GNP-NKCT1 might be a good source for anti-carcinoma and anti-tumor agents.
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Volumes & issues
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Volume 21 (2024)
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Volume 20 (2023)
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Volume 19 (2022)
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Volume 18 (2021)
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Volume 17 (2020)
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Volume 16 (2019)
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Volume 15 (2018)
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Volume 14 (2017)
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Volume 13 (2016)
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Volume 12 (2015)
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Volume 11 (2014)
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Volume 10 (2013)
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Volume 9 (2012)
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Volume 8 (2011)
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Volume 7 (2010)
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Volume 6 (2009)
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Volume 5 (2008)
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Volume 4 (2007)
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Volume 3 (2006)
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Volume 2 (2005)
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Volume 1 (2004)