Biomedical subjects

You Han Bae

Publications and source records attributed to You Han Bae.

At least 19 recordsLinked to original sources

PubMed2006

Polymer architecture and drug delivery.

Polymers occupy a major portion of materials used for controlled release formulations and drug-targeting systems because this class of materials presents seemingly endless diversity in topology and chemistry. This is a crucial advantage over other classes of materials to meet the ever-increasing requirements of new designs of drug delivery formulations. The polymer architecture (topology) describes the shape of a single polymer molecule. Every natural, seminatural, and synthetic polymer falls into one of categorized architectures: linear, graft, branched, cross-linked, block, star-shaped, and dendron/dendrimer topology. Although this topic spans a truly broad area in polymer science, this review introduces polymer architectures along with brief synthetic approaches for pharmaceutical scientists who are not familiar with polymer science, summarizes the characteristic properties of each architecture useful for drug delivery applications, and covers recent advances in drug delivery relevant to polymer architecture.

Animals↗

PubMed2006

Development of a sustained-release system for perivascular delivery of dipyridamole.

Vascular access grafts implanted in dialysis patients are prone to failure in the long-term because of stenosis and occlusion caused by neointimal hyperplasia. Local delivery of antiproliferative drugs may be effective to prevent this consequence while minimizing the systemic side effects they cause. We developed a combination of poly(lactide-co-glycolide) (PLGA) microspheres with ReGel, an injectable copolymer, as a sustained-release system for perivascular delivery of an antiproliferative drug, dipyridamole. Dipyridamole-incorporated PLGA microspheres with various molecular weights (MWs) of PLGA were prepared by oil-in-water emulsion method. Encapsulation efficiency and surface morphology of microspheres were characterized. In vitro release kinetics of dipyridamole from ReGel or from microspheres/ReGel was experimentally determined. Without microspheres, 40% of the dipyridamole was released from ReGel as an initial burst in the first 3 days followed by continuous release in the subsequent 2 weeks. The use of PLGA microspheres decreased the initial burst and extended dipyridamole release from 23 to 35 days with increasing MW of PLGA. The highest MW PLGA showed a lag time of 17 days before consistent drug release occurred. Mixing microspheres and ReGel with two different MW PLGA achieved a continuous release for 35 days with little initial burst. In vivo release of dipyridamole from microspheres/ReGel exhibited a comparable release pattern to that seen in vitro. This injectable platform is a promising technique for sustained perivascular delivery of antiproliferative drugs.

Animals↗

PubMed2006

Polymeric gene transfection on insulin-secreting cells: sulfonylurea receptor-mediation and transfection medium effect.

PURPOSE: In vitro transfection of secreting cells is regarded as one strategy for improved cell engineering/ transplantation. Insulin-secreting insulinoma cell lines or pancreatic beta-cells could be genetically engineered using designed polymeric vectors which are safer than viral vectors. This study investigates the effects of the constituents in transfection media on polymeric transfection. METHODS: Polyplexes conjugated with sulfonylurea (SU) were evaluated under different transfection conditions for gene transfection and their effects on cytotoxicity and insulin secretion. Several components in transfection media specifically associated with the insulin secretion pathway were amino acids, vitamins, Ca2+ and K+. The interactions of the polyplexes with insulin were monitored by surface charge and particle size to monitor how insulin as a protein influences transfection. RESULTS: For an insulin-secreting cell line (RINm5F), polyplexes in Ca2+--containing KRH medium (Ca2+(+)KRH) enhanced transfection and did not cause damage to biological functions. When adding amino acids, vitamins, or K+ or depleting Ca2+ from Ca2+(+)KRH, poly(L-lysine)/DNA complexes showed a greater reduction in transfection than SU receptor (SUR)-targeting polyplexes (SU-polyplex). Positively charged polyplexes interacted with insulin, developing a negative surface charge, and these interactions may cause a decrease in transfection. CONCLUSION: The findings suggest that in vitro and ex vivo polymeric transfection of insulin-secreting cells can be modulated and enhanced by adjusting the transfection conditions.

ATP-Binding Cassette Transporters↗

PubMed2006

pH-responsive sulfonamide/PEI system for tumor specific gene delivery: an in vitro study.

The feasibility of pH-sensitive polymeric nanoparticles that effectively target the acidic extracellular matrix of tumors is demonstrated. Plasmid DNA was complexed with polyethyleneimine (PEI) and further with a pH-sensitive diblock copolymer, poly(methacryloyl sulfadimethoxine) (PSD)-block-PEG (PSD-b-PEG), to obtain naonparticles. The shielding/deshielding of nanoparticles was tested along with cell viability and transfection efficiency at physiological and tumor pH. The nanoparticles composed of DNA/PEI/PSD-b-PEG were 300 nm in size and showed low cytotoxicity and transfection at pH 7.4 due to shielding of PEI by PSD-b-PEG. The PSD-b-PEG bound to PEI/DNA complex decreased the interaction of PEI positive charges with cells and reduced the cytotoxicity by 60%. At pH 6.6, the nanoparticles demonstrated high cytotoxicity and transfection, indicating PSD-b-PEG detachment from the nanoparticles and permit PEI to interact with cells. PSD-b-PEG is able to discern the small difference in pH between normal and tumor tissues and hence has remarkable potential in drug targeting to tumor areas.

Cations↗

PubMed2006

Thermogelling aqueous solutions of alternating multiblock copolymers of poly(L-lactic acid) and poly(ethylene glycol).

We are reporting alternating multiblock copolymers of poly(L-lactic acid)/poly(ethylene glycol) aqueous solution (> 15 wt %) undergoing sol-gel-sol transition as the temperature increases from 20 to 60 degrees C. Micelles of the multiblock copolymers (in water) are about 20 nm in radius at low temperature. They are aggregated to a larger size as the temperature increases, which should play a critical role in the sol-to-gel transition. The transition temperature and gel window were affected by the molecular weight and composition of the multiblock copolymer. In particular, the aqueous solution of an alternating multiblock copolymer (Mn approximately 6700 daltons) prepared from poly(ethylene glycol) (Mn approximately 600 daltons) and poly(L-lactic acid) (Mn approximately 1300 daltons) showed a maximum modulus at body temperature (37 degrees C). The in situ gel forming ability of the polymer aqueous solution in vivo as well as in vitro indicates that it can be a promising injectable biomaterial.

Animals↗

PubMed2006

Stimuli-sensitive polymeric micelles as anticancer drug carriers.

Amphiphilic block copolymers often form core-shell type micelles by self-organization of the blocks in an aqueous medium or under specific experimental conditions. Polymeric micelles constructed from these polymers that contain a segment whose physical or chemical properties respond to small changes in environmental conditions are collectively called 'stimuli-sensitive' micelles. This class of nano-scaled constructs has been investigated as a promising anti-cancer drug carrier because the micelles are able to utilize small environmental changes and modify drug release kinetics, biodistribution and the interactions with tissues and cells. This review summarizes the recent progress in stimuli-sensitive micelles for tumor chemotherapy, particularly for those responding to hyperthermic conditions, tumor pH and endosomal/lysosomal pH.

Animals↗

PubMed2005

pH-induced micelle formation of poly(histidine-co-phenylalanine)-block-poly(ethylene glycol) in aqueous media.

Poly[(L-histidine)-co-(L-phenylalanine)]-block-poly(ethylene glycol) (HF-b-PEG) diblock copolymers were synthesized to be used for preparation of pH-sensitive polymeric micelles. First, HF block was synthesized by ring opening copolymerization of L-histidine and L-phenylalanine N-carboxyanhydride, and then the resulting copolymer was coupled with PEG. The pKa value of diblock copolymer can be controlled by adjusting the histidine/phenylalanine ratio in HF block. It is observed that the block copolymers form micelles in aqueous media and that the micelles are spherical in shape with a unimodal distribution. The micelle is formed at pH higher than pKa of block copolymer while it is not formed at lower pH. This is because the protonation of histidine residue in the HF block converts the hydrophobic core into hydrophilic one at lower pH. Acid-Base titration profile of HF41(5600)-b-PEG, HF56(5500)-b-PEG, H(5100)-b-PEG and 0.1 N NaCl.

Drug Carriers↗

PubMed2005

Stability of bovine serum albumin complexed with PEG-poly(L-histidine) diblock copolymer in PLGA microspheres.

The aim of this study was to examine the stability of bovine serum albumin (BSA) in poly(DL-lactic acid-co-glycolic acid) (PLGA) microspheres upon addition of a new excipient, poly(ethylene glycol)-poly(L-histidine) diblock copolymer (PEG-PH). Poly(L-histidine) component can form an ionic complex with BSA under acidic conditions within a narrow pH range. To optimize the ionic complexation conditions for BSA with PEG-PH, the resulting complex sizes were monitored using the Zetasizer. PLGA microspheres containing BSA as a model protein were prepared by w/o/w double emulsion method. BSA stability in aqueous solutions and after release from PLGA microspheres was determined using circular dichroism (CD) spectroscopy for secondary structure analyses and fluorescence measurements for tertiary structure analyses. The release profile of BSA from the microspheres was monitored using UV spectrophotometry. The rate of PLGA degradation was monitored by gel permeation chromatography. The pH profile within microspheres was further evaluated by confocal microscopy using a pH-sensitive dye. Approximately 19 PEG-PH molecules and one BSA molecule coalesced to form an ionic complex around a pH range of 5.0-6.0. Plain BSA/PLGA and BSA/PEG-PH/PLGA microspheres had a mean size of 27-35 microm. PLGA microspheres with a BSA loading efficiency >80% were prepared using the double emulsion method. PEG-PH significantly improved the stability of BSA both in aqueous solutions and in PLGA microspheres. The release profiles of BSA from different formulations of PLGA microspheres were significantly different. PEG-PH effectively buffered the local acidity inside the microspheres and improved BSA release kinetics by reducing initial burst release and extending continuous release over a period of time, when encapsulated as an ionic complex. PLGA degradation rate was found to be delayed by PEG-PH. There was clear evidence that PEG-PH played multiple roles when complexed with BSA and incorporated into PLGA microspheres. PEG-PH is an effective excipient for preserving the structural stability of BSA in aqueous solution and BSA/PLGA microspheres formulation.

Drug Stability↗

PubMed2005

Biodegradable thermo-sensitive nanoparticles from poly(L-lactic acid)/poly(ethylene glycol) alternating multi-block copolymer for potential anti-cancer drug carrier.

In order to produce biodegradable thermo-sensitive nanoparticles, alternating multi-block copolymers (MBC) were synthesized by coupling dicarboxylated poly(ethylene glycol) (PEG; M(w) 2000) with poly(L-lactic acid) (PLLA)/PEG/PLLA triblock copolymers. Three different multi-block copolymers were synthesized by varying PLLA molecular weight (800 (MBC1), 1600 (MBC2), and 2800 (MBC3)). The MBC formed self-assembled nanoparticles with a unimodal size distribution during a dialysis process. The nanoparticles (NP) had a spherical shape with a size range of 90-330 nm in diameter and critical aggregation concentrations in a range of 5.6-12.6 microg/mL, depending on PLLA length in MBC. The thermo-sensitivity of MBC NP was monitored by the changes in particle size and interior structure as a function of temperature. The particle size slightly decreased as increasing temperature from 37 to 42 degrees C. The interior structure of the NP responded to temperature by altering microviscosity. The microviscosity, measured by the anisotropy (r value) of a fluorescence probe, of MBC1 NP significantly changed with increasing temperature (r = 0.187 at 25 degrees C and 0.216 at 42 degrees C), while MBC2 and MBC3 showed negligible changes in the microviscosity. This indicates that the temperature-dependent interior structure of the NP relied on the portion of PLLA in MBC. The thermo-sensitivity affected to the drug release behavior and cell cytotoxicity. At 42 degrees C, doxorubicin (DOX) loaded MBC1 NP showed enhanced cytotoxicity (approximately 20 times) against Lewis Lung Carcinoma (LLC) cells when compared to that at 37 degrees C.

Animals↗

PubMed2005

Polymeric gene carrier for insulin secreting cells: poly(L-lysine)-g-sulfonylurea for receptor mediated transfection.

Ex vivo transfer of therapeutic genes to cells is one of the potential strategies to prolong the life span of cell transplants. However, relatively safe non-viral carriers have not been extensively investigated due to their lower transfection efficiency. In this study, poly(L-lysine)-g-sulfonylurea varying SU content (PLL-SU) was synthesized to promote gene delivery efficacy to an insulin secreting cell line, RINm5F, which is known to express sulfonylurea receptor (SUR). The polymer formed complexes with a model reporter gene of pCMV-Luc (DNA) and the size of resulting particles was around 100 nm. The transfection efficiency of a polymer synthesized with 5 mol% of SU in the reaction feed (PLL-SU5%) to RINm5F cell was at least 5 times higher than that of PLL. The cytotoxicity of PLL-SU5%/DNA complex was equivalent to that of PLL/DNA complex. PLL-SU5% showed less transfection efficiency than PLL to NIH3T3 and HepG2 cells which are SUR negative. In RINm5F cells, the addition of free SU decreased the transfection efficiency of PLL-SU5%/DNA complex, suggesting that the complex shares the same receptors for SU. The PLL-SU5%/DNA complex seems to be internalized via SUR-mediated endocytosis pathway as suggested by vacuolar ATPases inhibition by Bafilomycin A1. It is noted that RINm5F cells treated with PLL-SU5%/DNA complex secreted more insulin than control, untreated cells, suggesting the insulinotropic effect of SU in PLL-SU5%. In conclusion, PLL-SU may be useful for transfer of therapeutic genes into insulin secreting cells.

Animals↗

PubMed2005

Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor.

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.

Animals↗

PubMed2005

Synthesis, bioactivity and specificity of glucagon-like peptide-1 (7-37)/polymer conjugate to isolated rat islets.

In order to increase the functionality of islets encapsulated in a biohybrid artificial pancreas (BAP), it was proposed that co-encapsulation with insulinotropic agents would improve insulin secretion from islets. To prevent agents from leaking out, conjugation with high-molecular-weight polymers was inevitable. In this study, synthetic glucagon-like peptide-1 (GLP-1) (7-37) was conjugated to a water-soluble polymer, poly(N-vinyl-2-pyrroridone-co-acrylic acid) (5 mol% acrylic acid, M(w) 445 kDa), via poly(ethylene glycol, M(w) 3.4 kDa) spacer. The chemical conjugation was confirmed by reverse phase-HPLC and the GLP-1 content in the GLP-1/polymer conjugate (VAPG) was determined by UV spectrophotometry at 280 nm (ca. 29 wt/wt%). In a static insulin secretion test, the VAPG increased insulin secretion up to 200% over a control (no stimulation) at high glucose levels, although the insulinotropic activity of VAPG was slightly lower than that of native GLP-1. The bioactivity of VAPG was prolonged for at least 2 weeks, which was examined by co-encapsulation of the conjugate into islet microcapsules. Dose-response curve revealed that the half-maximal effective dose (ED(50)) of VAPG was about 55 nm (25 nm for native GLP-1). By N-terminal analysis using aminopeptidase and RP-HPLC, it was confirmed that the lowered bioactivity of VAPG stemmed from the polymer conjugation to N-terminal histidine moieties, which actively participate in binding to GLP-1 receptors, resulting in only 16% of N-terminal histidine remaining intact after the conjugation reaction. Finally, the specific interaction of the VAPG with isolated rat islets was investigated. Total cellular cyclic AMP levels were measured and confocal microscopy was conducted using GLP-1 and VAPG labeled with fluorescent probes. It was found that VAPG effectively increased the cAMP level in islet cells in a glucose concentration-dependent manner. Moreover, the confocal microscopy study showed that the binding of VAPG occurs at the same location where GLP-1 binds but with less affinity than that of native GLP-1. In summary, a GLP-1/polymer conjugate was synthesized for the first time, and its bioactivity was examined, which must result from its specific interaction with isolated islets.

Animals↗

PubMed2005

Super pH-sensitive multifunctional polymeric micelle.

To endow enhanced tumor specificity and endosome disruption property on the carrier, a multifunctional polymeric micelle was investigated. The micelle exposes the cell interacting ligand (biotin) on the surface under slightly acidic environmental conditions of various solid tumors and is internalized by biotin receptor-mediated endocytosis in a short time period. The micelle also showed pH-dependent dissociation, causing the enhanced release of doxorubicin from the carrier in early endosomal pH. The dissociated micellar components subsequently disrupt endosomal membrane.

Adenocarcinoma↗

PubMed2005

Improved phenotype of rat islets in a macrocapsule by co-encapsulation with cross-linked Hb.

A number of rat islets were co-encapsulated in a diffusion chamber-type device, i.e., macrocapsule, with a thermoreversible polymeric extracellular matrix (ECM) and bioactive ingredient of cross-linked hemoglobin (Hb-C). The ECM was formed from an aqueous solution of N-isopropyl-acrylamide co-polymers with a small amount of acrylic acid, which exhibited unique sol-gel transition in a temperature range of 30-34 degrees C, without noticeable hysteresis. The incorporation of Hb-C in the islet macrocapsule showed a concentration-dependent effect on insulin secretion and viability of the entrapped islets. Insulin secretion stimulation by glucose and cell viability were more than doubled when compared with a control group (without Hb-C), at an optimum Hb-C concentration of 0.25 mM due to its unique oxygen transporting capacity. Furthermore, 0.25 mM Hb-C in the macrocapsule was able to support islet density up to 1000 islets/device in a 154 microl total volume without negative effects on islet functionality and viability. Hb-C incorporation is an effective strategy for a macrocapsule-type biohybrid artificial pancreas for Type-I diabetes treatment, which can be further developed to a rechargeable system by employing the thermoreversible ECM and designing a proper macrocapsule.

Animals↗

PubMed2005

Polymeric gene carriers.

Polymeric gene carriers are a potential alternative to using viral vectors. Polymeric carriers have relatively low immunogenicity and cytotoxicity. In addition, polymeric carriers can accommodate large-size DNA, be conjugated with appropriate functionalities, and be administered repeatedly. In spite of these advantages, polymeric gene carriers have some limitations, such as low gene transfection efficiencies and relatively short duration of gene expression. Therefore, extensive research has been conducted toward the development of efficient polymeric carriers. In this review, we discuss current problems associated with polymeric gene carriers and various strategies against transfection barriers in particular, gene stabilization and protection, cellular targeting, endosomal escaping, nuclear targeting, unpackaging, and biocompatibility. Finally, requirements for future polymeric gene carriers are considered. With all these ongoing efforts, polymeric carriers have become one of the promising gene delivery methods for human gene therapy.

Animals↗

PubMed2004

Prolonged glucose normalization of streptozotocin-induced diabetic mice by transplantation of rat islets coencapsulated with crosslinked hemoglobin.

BACKGROUND: Facilitated oxygen transport by crosslinked hemoglobin (Hb-C) in islet microcapsules may promote transplanted graft function by improving islet functionality and viability. METHODS: This study investigated the in vivo efficacy of Hb-C as an oxygen carrier on the functionality and viability of microencapsulated rat islets. Hb-C by poly(ethylene glycol) was introduced into rat islet microcapsules (alginate-poly[L-lysine]-alginate microcapsule), and 500 suboptimal encapsulated islets were xenotransplanted into each streptozotocin-induced diabetic BALB/c mouse. The graft efficacy over time was evaluated by measuring nonfasting blood glucose level, body weight, and glucose tolerance. RESULTS: Mice that received Hb-C-containing microcapsules maintained normoglycemia for at least 8 weeks with normal glucose clearance, determined by intraperitoneal glucose tolerance test. However, the mice that received the conventional control islet microcapsule (without Hb-C) transplant showed graft failure in 4 weeks, exhibited by hyperglycemia, weight loss, and deteriorated glucose tolerance. Severe central necrosis of retrieved islets was observed for the control islet capsule graft after 8 weeks. CONCLUSION: The present study revealed that the incorporation of Hb-C in islet microcapsules promotes graft function for a longer period of time than the conventional islet capsules. Therefore, Hb-C coencapsulation is a potential approach for prolonging graft function of islet microcapsules and reducing the number of islets required for normoglycemia.

Animals↗

PubMed2004

Synthesis of biodegradable multi-block copolymers of poly(L-lysine) and poly(ethylene glycol) as a non-viral gene carrier.

Biodegradable and non-toxic multi-block copolymers based on poly(L-lysine) and poly(ethylene glycol) were synthesized. Synthesized copolymers showed almost negligible cytotoxicity above 95% cell viability and transfection efficiency compared to the PLL homopolymer with molecular weight of 25,700. Biodegradation under physiological conditions revealed that the molecular weight of copolymers decreased to 20% of the initial molecular weight within 72 h. Transfection efficiencies of copolymers were not affected by the presence of serum, while that of PLL homopolymer decreased to the level of naked DNA in the presence of serum. Based on the results, the new copolymers are believed to be a potentially efficient carrier for the delivery of bioactive agents.

Cell Line, Transformed↗

PubMed2004

pH-sensitivity and pH-dependent interior structural change of self-assembled hydrogel nanoparticles of pullulan acetate/oligo-sulfonamide conjugate.

pH-sensitive hydrogel nanoparticles that respond to the local acidic pH found in various diseased states such as tumors, ischemia and inflammation were prepared from pullulan acetate/oligo-sulfadimethoxine (PA/OSDM) conjugates. PA/OSDM nanoparticles prepared by dialysis at pH 9.5 had a spherical shape with a size range of 50-140 nm and low critical aggregation concentration (CAC) (<12 x 10(-3) mg/ml), dependent on the degree of substitution of OSDM (DS). With a decrease in dialysis pH (pHdia), the CAC gradually decreased due to the increase in the hydrophobic nature of OSDM. The nanoparticles prepared at pHdia 8.0 from the polymer with DS 1.0 aggregated in a pH range of 6.6-7.2 while the aggregation of nanoparticles prepared below pHdia 7.4 occurred in a broader pH range with a downshifted transition pH. These results indicate that the CAC and sharpness of the pH sensitivity of self-assembled hydrogel nanoparticles can be controlled by the pH of the dialysis buffer. In addition, the photophysical and photochemical characteristics of the nanoparticles were examined by a fluorescence probe technique. The micropolarity was monitored by pyrene and the microviscosity was measured by 1,6-diphenyl-1,3,5,-hexatriene (DPH) in the core of nanoparticles. Both properties dramatically changed as the pH decreased from 7.2 to 6.8, indicating that the interior restructuring of the hydrogel nanoparticles changed rapidly in this pH range. This is probably due to recruitment of hydrophobic group of deionized OSDM into the core. The pH sensitivity of the nanoparticles affected their drug release behavior. Doxorubicin (DOX) release from the PA/OSDM nanoparticles showed pH-dependent profiles around physiological pH and was significantly promoted at pH<6.8.

Acetates↗