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Direct micro-patterning of biodegradable polymers using ultraviolet and femtosecond lasers
Aguilar, C. A., Y. Lu, et al. (2005), Biomaterials 26(36): 7642-9.
Abstract: Thin films of biodegradable polymeric materials, poly(epsilon-caprolactone) (PCL) and poly(glycolic acid) (PGA) were micro-patterned using a Ti-sapphire femtosecond pulsed laser and ArF excimer UV laser in ambient conditions. The laser-patterned polymers were characterized using a scanning electron microscope (SEM), Fourier transform infrared spectroscopy in attenuated total reflectance mode (FTIR-ATR) and X-ray photoelectron spectroscopy (XPS). In-vitro degradation tests were performed and the laser-patterned samples showed to be within one standard deviation of the control samples. Our results demonstrate that both lasers are excellent tools for micro-patterning biodegradable polymers since the bulk properties of the material can remain intact and because the direct-write method is rapid, flexible, and a chemical-free process.

Direct patterning of mammalian cells onto porous tissue engineering substrates using agarose stamps
Stevens, M. M., M. Mayer, et al. (2005), Biomaterials 26(36): 7636-41.
Abstract: This paper describes simple, inexpensive, and potentially generic methodology for generating patterns of mammalian cells on porous scaffolds for tissue engineering using replica printing. Circular patterns (diameter: 200, 700, and 1000 microm) of human osteoblasts were transferred directly from topographically patterned agarose stamps onto porous hydroxyapatite scaffolds or onto fibronectin-coated glass slides. The use of hydrogel stamps provided a "wet", biocompatible surface and maintained the viability of cells adsorbed on stamps during the patterning process. Stamps inked once with suspensions of cells allowed the repeated patterning of substrates. Direct stamping of human osteoblasts (and, potentially other mammalian cells) can be used to control the size, spacing, and geometry of patterns of cells printed on porous tissue engineering substrates. This approach may find use in controlling the spatial invasion of scaffolds, promoting the hierarchical organization of cells, and in controlling cell-cell interactions as a step in preservation of phenotypes of cells.

Directed cell migration via chemoattractants released from degradable microspheres
Zhao, X., S. Jain, et al. (2005), Biomaterials 26(24): 5048-63.
Abstract: Chemotaxis, cell migration directed by spatial concentration gradients of chemoattractant molecules, is critical for proper function of the immune system. Materials capable of generating defined chemoattractant gradients via controlled release may be useful for the design of improved vaccines and immunotherapies that draw specific cells to an immunization site. To this end, we encapsulated formyl-Nle-Leu-Phe-Nle-Tyr-Lys (fN'LFN'YK) peptides or macrophage inflammatory protein-3alpha (MIP-3alpha or CCL20) in degradable poly(lactide-co-glycolide) microspheres that provided sustained release for more than 2 weeks in vitro. fN'LFN'YK and MIP-3alpha chemoattract dendritic cells (DCs), the key antigen-presenting cells involved in generation of primary immune responses, and their precursors, monocytes. Using an in vitro videomicroscopy migration assay, we detected strong chemotaxis of human monocytes and monocyte-derived DCs through 3D collagen gels toward microspheres releasing fN'LFN'YK. Similarly, microparticles releasing MIP-3alpha were able to attract mouse bone marrow-derived dendritic cells. Strikingly, prolonged attraction of DCs from distances up to 500 microm from the source to the point of contact with individual microspheres was observed. Such microspheres could be of general interest for the design of vaccines that promote adaptive immunity and as a platform for studying the biology of chemotaxis in vitro and in vivo.

Directional guidance of neurite outgrowth using substrates patterned with biomaterials
Matsuzawa, M., V. Krauthamer, et al. (1995), Biosystems 35(2-3): 199-202.
Abstract: The use of geometrically simple networks formed by cultured neurons facilitates the electrophysiological study of biological computation. We used chemically patterned substrates for culturing SK-N-SH human neuroblastoma cells and embryonic rat hippocampal neurons to geometrically control their neurite outgrowth. On patterned substrates (parallel lines, 5-10 microns width), the neuroblastoma cells developed bipolar morphology with long neurite processes (approximately 200 microns) in the presence of retinoic acid. Hippocampal neurons cultured on substrates of hexagonal patterns extended their neurites preferentially along the circumferences of the hexagons and formed geometrically well defined network structures.

Directional neurite outgrowth is enhanced by engineered meningeal cell-coated substrates
Walsh, J. F., M. E. Manwaring, et al. (2005), Tissue Eng 11(7-8): 1085-94.
Abstract: After injury to the CNS, the anatomical organization of the tissue is disrupted, posing a barrier to the regeneration of axons. Meningeal cells, a central participant in the CNS tissue response to injury, migrate into the core of the wound site in an unorganized fashion and deposit a disorganized extracellular matrix (ECM) that produces a nonpermissive environment. Previous work in our laboratory has shown that the presentation of nanometer-scale topographic cues to these cells influences their morphological, cytoskeletal, and secreted ECM alignment. In the present study, we provided similar environmental cues to meningeal cells and examined the ability of the composite construct to influence dorsal root ganglion regeneration in vitro. When grown on control surfaces of meningeal cells lacking underlying topographic cues, there was no bias in neurite outgrowth. In contrast, when grown on monolayers of meningeal cells with underlying nanometer-scale topography, neurite outgrowth length was greater and was directed parallel to the underlying surface topography even though there exists an intervening meningeal cell layer. The observed outgrowth was significantly longer than on laminin-coated surfaces, which are considered to be the optimal substrata for promoting outgrowth of dorsal root ganglion neurons in culture. These results suggest that the nanometer-level surface finish of an implanted biomaterial may be used to organize the encapsulation tissue that accompanies the implantation of materials into the CNS. It furthermore suggests a simple approach for improving bridging materials for repair of nerve tracts or for affecting cellular organization at a device-tissue interface.

Dissolution and mineralization of sintered and thermally sprayed hydroxy-fluoroapatites
Pullen, L. J. and K. A. Gross (2005), J Mater Sci Mater Med 16(5): 399-404.
Abstract: Hydroxyapatites are commonly used as bone cement, coatings on implants for dental and orthopaedic applications, but also as middle ear implants. These applications all require a different tissue healing response that can be attained by different manufacturing processes or by chemically modifying the composition. During implantation apatites undergo a process of dissolution and mineralization. The degree of dissolution is dependent upon the manufacturing process & is higher for thermally sprayed implant materials. This allows them to integrate to the natural bone. This study tests the dissolution and mineralization of fluoride containing hydroxyapatites through immersion in simulated body fluid. It shows that mineralization occurs more readily in hydroxyapatites than fluorapatites because of their higher dissolution rate. Mineralization was detected most readily by image analysis using scanning electron microscopy than by weight changes using a microbalance. Microscopy allowed small heterogeneous precipitates to be observed during the initial stages of mineralization.

Distribution patterns of the membrane glycoprotein CD44 during the foreign-body reaction to a degradable biomaterial in rats and mice
Bonnema, H., E. R. Popa, et al. (2003), J Biomed Mater Res A 64(3): 502-8.
Abstract: Although biomaterials have been used in the clinical setting for a long time, little is known of the molecular mechanisms underlying the foreign-body reaction (FBR). A good understanding of these mechanisms is requisite for the controlled regulation of the FBR needed to prevent adverse tissue reactions and thus to improve the function of the biomaterial. Macrophages are essential in the inflammatory reaction in, as well as around, the implants, and they also are believed to initiate most of the adverse responses. Typically, during the FBR macrophages become activated and fuse into multinucleated giant cells (MnGCs). CD44, an integral membrane glycoprotein expressed on a broad spectrum of cell types, is involved in MnGC formation in vitro and in inflammation processes in general. In vivo it is not known whether CD44 is part of a specific protein machinery that enables macrophage fusion or whether it has additional functions in the FBR. In the present in vivo study, CD44 expression patterns were followed in rats and mice during the FBR to a degradable collagen type I biomaterial. We found that CD44 is upregulated on all migrating cells and on newly formed blood vessels at the onset of the FBR and that MnGCs, up to week 15 postimplantation, expressed CD44. Although no evidence was found that CD44 participates in macrophage fusion leading to multinucleation, it nevertheless may be an interesting target molecule for modulating the FBR in vivo, possibly by affecting cell activation, cell migration towards the biomaterial, vascularization, and MnGC formation.

DNA biosensor based on chitosan film doped with carbon nanotubes
Li, J., Q. Liu, et al. (2005), Anal Biochem 346(1): 107-14.
Abstract: A biosensor based on chitosan doped with carbon nanotube (CNT) was fabricated to detect salmon sperm DNA. Methylene blue (MB) was employed as a DNA indicator. It was found that CNTs can enhance the electroactive surface area threefold (0.28 +/- 0.03 and 0.093 +/- 0.06 cm(2) for chitosan-CNT- and chitosan-modified electrodes, respectively) and can accelerate the rate of electron transfer between the redox-active MB and the electrode. A low detection limit of 0.252 nM fish sperm DNA was achieved, and no interference was found in the presence of 5 microg/ml human serum albumin. The differential pulse voltammetry signal of MB was linear over the fish sperm DNA concentration range of 0.5-20 nM.

DNA multilayer films on planar and colloidal supports: sequential assembly of like-charged polyelectrolytes
Johnston, A. P., E. S. Read, et al. (2005), Nano Lett 5(5): 953-6.
Abstract: Multilayer films comprising solely negatively charged polyelectrolytes were sequentially assembled based on DNA hybridization. Films prepared from alternating layers of two-block homopolymeric nucleotides (polyA(20)G(20)/polyT(20)C(20)) grew linearly with increasing layer number, as verified by quartz crystal microgravimetry, UV-vis spectrophotometry and optical microscopy. Urea treatment of the films induced morphological changes, while exposure to low ionic strength solutions resulted in film disassembly. DNA multilayer films were also formed on silica particles, and DNA hollow capsules were obtained following dissolution of the template core.

DNA probe identification of bacteria colonizing internal surfaces of the implant-abutment interface: a preliminary study
Callan, D. P., C. M. Cobb, et al. (2005), J Periodontol 76(1): 115-20.
Abstract: BACKGROUND: Currently, there is limited knowledge concerning the specific genus and species of bacteria that may colonize internal surfaces of the implant-abutment interface (IAI) of two-stage dental implants. The purpose of this study was to use DNA probe analysis to identify those periodontopathic bacteria that may inhabit the internal surfaces and healing abutment screw-threads of the IAI of dental implants in situ. METHODS: Following osseointegration, bacterial samples for DNA probe analysis were obtained from 54 two-stage hydroxyapatite plasma spray-coated implants in 32 patients. Using sterile paper points, samples were obtained from the IAI of 43 implants and the screw-threads of healing abutments in the other 11 implants. DNA probes were available to detect the following microbes: Actinobacillus actinomycetemcomitans, Tannerella forsythensis, Campylobacter rectus, Eikenella corrodens, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, and Treponema denticola. RESULTS: All samples taken from healing abutment screw-threads were negative for all target microbes. The aggregate percentage of positive results for each target microbe for samples from internal surfaces of the IAI were: 41.9%, A. actinomycetemcomitans, 60.5%, T. forsythensis; 44.2%, C rectus; 60.5%, E. corrodens; 48.8%, F. nucleatum; 46.5%, P. gingivalis; 55.8%, P. intermedia; and 51.2%, T. denticola. In addition, no significant differences were noted between colonization of individual microbial species when comparing anterior to posterior and maxillary to mandibular implant sites. CONCLUSIONS: Moderate to high levels of eight different periodontopathic microbes inhabiting the internal surfaces of the IAI of 43 two-stage implants in partially edentulous patients were identified by DNA probe analysis. The microbes colonized these surfaces within 25 days following the second stage surgery and placement of the healing abutment. In contrast, all samples obtained from screw-threads of 11 healing abutments were DNA probe negative. These findings appear to support those of other investigations demonstrating the translocation of bacteria from residual dentition to implants.

DNA strands robed with ionic liquid moiety
Nishimura, N., Y. Nomura, et al. (2005), Biomaterials 26(27): 5558-63.
Abstract: An ionic liquid domain was successfully prepared outside double-stranded DNA by fixing 1-alkyl-3-methyl-imidazolium (C(n)MI) cations on the phosphate groups of DNA. First, four species of ionic liquid were made using phosphoric acid di-n-butyl ester and C(n)MI (n=2,4,8, and 12) as a low molecular weight model. They were obtained as liquid salts, and their ionic conductivity ranged up to 10(-5)Scm(-1) at 50 degrees C. Based on this model study, counter cations of the phosphate groups of DNA were exchanged for four kinds of imidazolium cations. The resulting ionic liquid-robed DNA (IL-robed DNA) was soluble in ordinary organic solvents such as methanol or ethanol. Ionic conductivity was low, because the ion density was insufficient to form a continuous ionic liquid domain around the DNA strands. When 11mol% 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIBF(4)), which is a typical ionic liquid, was mixed with the IL-robed DNA, an ionic conductivity of 5.4 x 10(-5) S cm(-1) at 30 degrees C was observed because a continuous ionic liquid domain was successfully formed.

Does cardiopulmonary bypass still represent a good investment? The biomaterials perspective
Gourlay, T. and P. Connolly (2003), Perfusion 18(4): 225-31.
Abstract: Cardiopulmonary (CPB) bypass is 50 years old this year, and has undergone considerable change in that time, particularly with regard to developing technology. However, in recent years the routine application of CPB, as the treatment of choice for patients undergoing reparative heart surgery, has been challenged by new, evolving techniques, particularly Off-Pump Coronary Artery Bypass (OPCAB) and stenting. This paper considers whether CPB still represents a sound investment prospect, with particular emphasis on the biomaterial developments currently taking place. Whilst we accept that routine application of CPB is shrinking under pressure from less invasive techniques, we suggest that this may represent an opportunity to deliever a more highly evolved perfusion to the core of very sick and complex patients who may not be suitable candidates for OPCAB or stenting. These patients will benefit from the application of new technologies currently under development, such as smaller perfusion circuits, improved biomaterial surfaces, smart membranes, and biosensor technology, all aimed at making clinical perfusion a safer and more predictable procedure for the patient. All things considered, we feel that CPB, although shrinking in absolute size, still represents a good investment.

Dog sciatic nerve regeneration across a 30-mm defect bridged by a chitosan/PGA artificial nerve graft
Wang, X., W. Hu, et al. (2005), Brain 128(Pt 8): 1897-910.
Abstract: We have developed a dual-component artificial nerve graft comprising an outer microporous conduit of chitosan and internal oriented filaments of polyglycolic acid (PGA). The novel graft was used for bridging sciatic nerve across a 30-mm defect in six Beagle dogs, which were used as a chitosan/PGA graft group. The other Beagle dogs were divided into an autograft group (n = 6) as the positive control and a non-grafted group (n = 5) as the negative control. All animals of three groups were monitored for changes in their appearance and locomotion activities after surgery. Their posture and gait were recorded regularly with the aid of photographs and videotapes for each dog. Six months post-operatively, a combination of electrophysiological examination, FluoroGold retrograde tracing, histological assessment including light microscopy and transmission electron microscopy, immunohistochemistry as well as morphometric analyses to both regenerated nerves and target muscles was utilized to investigate the nerve repair effects of our artificial nerve graft. The results demonstrated that, in the chitosan/PGA graft group, the dog sciatic nerve trunk had been reconstructed with restoration of nerve continuity and functional recovery, and its target skeletal muscle had been re-innervated, improving locomotion activities of the operated limb. This study proves the feasibility of the chitosan/PGA artificial nerve graft for peripheral nerve regeneration by bridging a longer defect in a large animal model.

Doped semiconductor nanomaterials
Chen, X., Y. Lou, et al. (2005), J Nanosci Nanotechnol 5(9): 1408-20.
Abstract: The development and properties of doped nanomaterials including doped titanium dioxide, doped silicon, and doped cadmium telluride are reviewed, as well as their ultrafast dynamics. Doping nanomaterials provides a flexible way to tune to the properties of the materials while maintaining their high surface areas. The electronic, optical, photochemical, photoelectrochemical, photocatalytic and photoexcited relaxation properties can be tuned towards the desired direction by doping different elements. The materials can be engineered towards specific applications through careful selection of the dopants.

Dose- and time-dependent effect of bioactive gel-glass ionic-dissolution products on human fetal osteoblast-specific gene expression
Christodoulou, I., L. D. Buttery, et al. (2005), J Biomed Mater Res B Appl Biomater 74(1): 529-37.
Abstract: Bioactive glasses dissolve upon immersion in culture medium, and release their constitutive ions into solution. There has been some evidence suggesting that these ionic-dissolution products influence osteoblast-specific processes. Here, the effect of 58S sol-gel-derived bioactive glass (60% SiO(2), 36% CaO, 4% P(2)O(5), in molar percentage) on primary osteoblasts derived from human fetal long bone explant cultures is investigated, and it is hypothesized that critical concentrations of sol-gel-dissolution products (consisting of a combination of simple inorganic ions) can enhance osteoblast phenotype in vitro by affecting the expression of a number of genes associated with the differentiation and extracellular matrix deposition processes. Cells were exposed to a range of 58S dosages continuously for a period of 4-14 days in monolayer cultures. Quantitative real-time RT-PCR analysis of a panel of osteoblast-specific markers showed a varied gene expression pattern in response to the material. The highest concentration of Ca and Si tested (96 and 50 ppm, respectively) promoted upregulation of gene expression for most markers (including alkaline phosphatase, osteocalcin, and osteopontin) at the latest time point, compared to non-58S-treated control, although this observation was not statistically significant. The same 58S concentration produced higher ALP activity levels and increased proliferation throughout the culture period, compared to lower dosages tested; however, the results generated were again not statistically significant. The data overall suggest that no significant effect can be ascribed to the ionic products of 58S bioactive gel-glass dissolution tested here and their ability to stimulate osteoblastic marker gene expression.

Dose-response relationships for radicals trapped in irradiated solids
Nelson, W. H. (2005), Radiat Res 163(6): 673-80.
Abstract: This work develops a modified description of the dose-response relationships for radical production by ionizing radiation. The main new feature is incorporation of the concept of the target and the possibility that the population of targets can undergo depletion at increased doses. The resulting mathematical relationships are capable of describing the decrease in product yield at increasing doses as is sometime observed. In addition, the description preserves the general properties of the widely used relationships. Finally, the expressions provide the possibility for estimating the average mass of the target.

Dosimetric study of a new polymer encapsulated palladium-103 seed
Bernard, S. and S. Vynckier (2005), Phys Med Biol 50(7): 1493-504.
Abstract: The use of low-energy photon emitters for brachytherapy applications, as in the treatment of prostate or ocular tumours, has increased significantly over the last few years. Several new seed models utilizing 103Pd and 125I have recently been introduced. Following the TG43U1 recommendations of the AAPM (American Association of Physicists in Medicine) (Rivard et al 2004 Med. Phys. 31 633), dose distributions around these low-energy photon emitters are characterized by the dose rate constant, the radial dose function and the anisotropy function in water. These functions and constants can be measured for each new seed in a solid phantom (i.e. solid water such as WT1) using high spatial resolution detectors such as very small thermoluminescent detectors. These experimental results in solid water must then be converted into liquid water by using Monte Carlo simulations. This paper presents the dosimetric parameters of a new palladium seed, OptiSeed (produced by International Brachytherapy (IBt), Seneffe, Belgium), made with a biocompatible polymeric shell and with a design that differs from the hollow titanium encapsulated seed, InterSource103, produced by the same company. A polymer encapsulation was chosen by the company IBt in order to reduce the quantity of radioactive material needed for a given dose rate, and to improve the symmetry of the radiation field around the seed. The necessary experimental data were obtained by measurements with LiF thermoluminescent dosimeters (1 mm3) in a solid water phantom (WT1) and then converted to values in liquid water using Monte Carlo calculations (MCNP-4C). Comparison of the results with a previous study by Reniers et al (2002 Appl. Radiat. Isot. 57 805) shows very good agreement for the dose rate constant and for the radial dose function. In addition, the results also indicate an improvement in isotropy compared to a conventional titanium encapsulated seed. The relative dose (anisotropy value relative to 90 degrees) from the seed at a distance of 3 cm is close to 70% at 0 degrees whereas that for the titanium encapsulated InterSource103seed is close to 40%. This paper also presents some new Monte Carlo calculations relating to shadowing produced by the seeds in an array implanted for a prostate cancer treatment. Recently, Mobit and Badragan (2004 Phys. Med. Biol. 49 3171) reported shadowing resulting in a 10% decrease in dose from titanium encapsulated 125I seed. We used Monte Carlo simulations (MCNP-4C) to evaluate shadowing for the InterSource103 titanium encapsulated seed and the OptiSeed polymer encapsulated seed. For a specific geometry specified, dose decreases of 13% and 7% were found for the InterSource103 titanium encapsulated and the OptiSeed polymer encapsulated seed, respectively.

Down regulation of degenerative cartilage molecules in chondrocytes grown on a hyaluronan-based scaffold
Grigolo, B., L. De Franceschi, et al. (2005), Biomaterials 26(28): 5668-76.
Abstract: Hyaluronic-acid-based biomaterials used for cartilage repair allow the expression of specific extracellular matrix molecules by human chondrocytes grown onto them. We investigated whether these biomaterials could also create an environment in which the cells downregulate the expression of some catabolic factors. Chondrocytes were isolated from human articular cartilage obtained from the knees of patients with a history of trauma. First, the cells were expanded in monolayers and then they were seeded on a hyaluronic-acid derivative scaffold. Constructs and surnatants were collected and analysed at 1, 3, 7, 14 and 21 days after seeding. Immunohistochemical analysis for CD44 and caspase was carried out on paraffin-embedded sections. The Tunel method was used to identify chondrocyte apoptosis status. Secretion of MMP-1 and MMP-13 in the surnatants of the cells grown onto the biomaterial was measured by enzyme-linked immunosorbent assay. Nitric oxide (NO) production was evaluated by estimating the stable NO metabolite nitrite by the Griess method. A real-time RT-PCR analysis was performed on the constructs to evaluate the expression of type I and II collagens, aggrecan, Sox-9, MMP-1 and MMP-13 mRNAs at the different experimental times evaluated. Decreased levels of metalloproteinases and nitric oxide were observed in the surnatants of chondrocytes grown onto the hyaluronan-based scaffold. This was also confirmed by real-time PCR analysis which showed that the cells expressed the specific differentiated phenotype downregulating the expression of some catabolic molecules. Cells apoptosis decreased during the culture period, which further supported the biochemical data. The ability of the hyaluronan scaffold to reduce the expression and production of molecules involved in cartilage degenerative diseases indicates its use to treat early lesions of osteoarthritic patients.

Down-regulation of CD9 in human ovarian carcinoma cell might contribute to peritoneal dissemination: morphologic alteration and reduced expression of beta1 integrin subsets
Furuya, M., H. Kato, et al. (2005), Cancer Res 65(7): 2617-25.
Abstract: Peritoneal dissemination is one of the main causes of death in cancer patients. Pathophysiology of metastasis has been well investigated, but the mechanism of diffuse spread of tumor colonies in the peritoneal cavity is not fully understood. CD9 is a member of tetraspanin and its down-regulation is known to be involved in poor prognosis. To investigate the significance of the down-regulation of CD9, HTOA, an ovarian carcinoma cell line that highly expressed CD9, was transiently transfected with small interfering RNA (siRNA) against CD9, and CD9-negative cells (HTOA(CD9-)) were purified. HTOA(CD9-) showed altered adhesion patterns on Matrigel, collagen, fibronectin, and laminin compared with those of control siRNA-transfected HTOA (control-HTOA). Flow cytometry and fluorescence cytostainings revealed that the expression levels of integrins beta1, alpha2, alpha3beta1, alpha5, and alpha6 were lower in HTOA(CD9-) than those of control-HTOA. HTOA(CD9-) showed altered expression of junctional and cytoskeletal molecules. By time-lapse video microscopy, control-HTOA showed solid adhesion to extracellular matrix and formed cobblestone pattern, whereas HTOA(CD9-) showed weaker adhesion and were distributed as diffuse spots. To examine whether the expression level of CD9 change during tumor dissemination, HTOA-P, a highly disseminative subclone of HTOA, was established. HTOA-P showed distinctive down-regulation of CD9 at mRNA and protein levels, and showed similar morphologic alteration as HTOA(CD9-) did. These findings indicate that the down-regulation of CD9 may be an acquired event in the process of tumor dissemination. Down-regulated CD9 may attenuate the expression of several integrins and rearrange junctional and cytoskeletal molecules that might contribute to dissemination of ovarian carcinomas.

Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor
Lee, E. S., K. Na, et al. (2005), J Control Release 103(2): 405-18.
Abstract: In order to overcome multidrug resistance in solid tumors, doxorubicin (DOX) loaded pH-sensitive micelles of which surface was decorated with folate (PHSM/f) were evaluated both in vitro and in vivo experiments. PHSM/f were fabricated from a mixture of two block copolymers of poly(L-histidine) (M(n): 5K)-b-PEG (M(n): 2K)-folate (polyHis/PEG-folate) (75 wt.%) and poly(L-lactic acid) (M(n): 3K)-b-PEG (M(n): 2K)-folate (PLLA/PEG-folate) (25 wt.%). The PHSM/f showed more than 90% cytotoxicity of DOX resistant MCF-7 (MCF-7/DOX(R)) when cultured with PHSM/f at a concentration of 10 microg/ml DOX. The result was interpreted by a sequential event of active internalization of PHSM/f via folate-receptor mediated endocytosis and ionization of His residues which result in micelle destabilization and probably disturbance of endosomal membranes. This potential mechanism may endow the drug carriers to bypass Pgp efflux pump and sequestration of DOX in acidic intracellular compartments, yielding high cytotyoxicity. Experimental evaluation of tumor regression was carried out in a small animal model bearing s.c. MCF-7 or MCF-7/DOX(R) xenografts. The tumor (MCF-7/DOX) volumes of mice treated with PHSM/f were significantly less than control groups treated with free DOX or similar micelles but without folate (PHSM). In the MCF-7/DOX(R) xenograft model, the accumulated DOX level of PHSM/f in solid tumors was 20 times higher than free DOX group, and 3 times higher than PHSM group. The results demonstrate that PHSM/f is a viable means for treating drug resistant tumors.

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Last Modified: 8 February 2006