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PubMed2001

Immunoconjugates of soybean Bowman-Birk protease inhibitor as targeted antitumor polymeric agents.

To enhance the antitumor potential of soybean Bowman-Birk inhibitor (BBI), the conjugate of BBI with an antibody via a macromolecular carrier was prepared. Clinical dextran (D) was used as a biocompatible biodegradable carrier for co-immobilization of BBI and antibody. A model immunoglobulin isolated from sheep serum (sIgG), raised against human IgM was utilized to develop the procedure of immunoconjugate synthesis. The molar ratio of the ingredients in the conjugate was the following BBI:D:sIgG=9:1:1. Comparison of the dose response curves for the native sIgG and the BBI-D-sIgG conjugate indicated that sIgG completely retained its specific activity (>90%) after modification with dextran. The determination of the Ki values for chymotrypsin interaction with the native BBI and the BBI-D-sIgG conjugate indicated high anti-chymotrypsin activity. In the next step, the monoclonal antibody (ICO 25 MAb) against the mucin-like human epithelial membrane antigen was used for conjugation as it is the most universal vector for targeting different agents to human tumors of epithelial origin. The influence of conjugation on the specificity of the Mab reaction with its antigen was studied. The conjugated MAb reacted with tumor cells of different epithelial genesis (breast, lung, gastric, ovarian and uterus tumors), but did not react with tumor cells of non-epithelial origin. It was shown that BBI-D-ICO 25 MAb conjugate has almost the same immunohistochemical activity as non-conjugated MAb. These results demonstrated the feasibility of exploiting the activities of covalently bound BBI and ICO 25 MAb for anticarcinogenic agent targeting.

Animals↗
PubMed2000

Effects of transforming growth factor beta1 released from biodegradable polymer microparticles on marrow stromal osteoblasts cultured on poly(propylene fumarate) substrates.

Recombinant human transforming growth factor beta1 (TGF-beta1) was incorporated into microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) to create a delivery vehicle for the growth factor. The entrapment efficiency of TGF-beta1 in the microparticles containing 5% PEG was 40.3 +/- 1.2% for a TGF-beta1 loading density of 6.0 ng/1 mg of microparticles. For the same loading, 17.9 +/- 0.6 and 32.1 +/- 2.5% of the loaded TGF-beta1 was released after 1 and 8 days, respectively, followed by a plateau for the remaining 3 weeks. Rat marrow stromal cells showed a dose response to TGF-beta1 released from the microparticles similar to that of added TGF-beta1, indicating the activity of TGF-beta1 was retained during microparticle fabrication and after TGF-beta1 release. An optimal TGF-beta1 dosage of 1.0 ng/mL was determined through a 3-day dose response study for maximal alkaline phosphatase (ALP) activity. The TGF-beta1 released from the microparticles loaded with 6.0 ng TGF-beta1/1 mg of microparticles for the optimal dosage of TGF-beta1 enhanced the proliferation and osteoblastic differentiation of marrow stromal cells cultured on poly(propylene fumarate) substrates. The cells showed significantly increased total cell number, ALP activity, and osteocalcin production with values reaching 138,700 +/- 3300 cells/cm(2), 22.8 +/- 1.5 x 10(-7) micromol/min/cell, and 15.9 +/- 1.5 x 10(-6) ng/cell, respectively, after 21 days as compared to cells cultured under control conditions without TGF-beta1. These results suggest that controlled release of TGF-beta1 from the PLGA/PEG blend microparticles may find applications in modulating cellular response during bone healing at a skeletal defect site.

Animals↗
PubMed2005

Cross-linked small polyethylenimines: while still nontoxic, deliver DNA efficiently to mammalian cells in vitro and in vivo.

PURPOSE: Polyethylenimine (PEI) is among the most efficient nonviral gene delivery vectors. Its efficiency and cytotoxicity depend on molecular weight, with the 25-kDa PEI being most efficient but cytotoxic. Smaller PEIs are noncytotoxic but less efficient. Enhancement in gene delivery efficiency with minimal cytotoxicity by cross-linking of small PEIs via potentially biodegradable linkages was explored herein. The hypothesis was that cross-linking would raise the polycation's effective molecular weight and hence the transfection efficiency, while biodegradable linkages would undergo the intracellular breakdown after DNA delivery and hence not lead to cytotoxicity. Toward this goal, we carried out cross-linking of branched 2-kDa PEI and its 1:1 (w/w) mixture with a linear 423-Da PEI via ester- and/or amide-bearing linkages; the in vitro and in vivo gene delivery efficiency, as well as toxicity to mammalian cells, of the resultant cross-linked polycations were investigated. METHODS: The efficiency of the cross-linked PEIs in delivering in vitro a plasmid containing beta-galactosidase gene and their cytotoxicity were investigated in monkey kidney cells (COS-7). Dynamic light scattering was used to compare the relative DNA condensation efficiency of the unmodified and cross-linked PEIs. In vivo gene delivery efficiency was evaluated by intratracheal delivery in mice of the complexes of a luciferase-encoding plasmid and the PEIs and estimating the luciferase expression in the lungs. RESULTS: Cross-linking boosted the gene delivery efficiency of the small PEIs by 40- to 550-fold in vitro; the efficiency of the most potent conjugates even exceeded by an order of magnitude that of the branched 25-kDa PEI. Effective condensation of DNA was evident from the fact that the mean diameter of the complexes of the cross-linked PEIs was some 300 nm with a narrow size distribution, while the complexes of the unmodified small PEIs exhibited a mean size of >700 nm with a very broad size distribution. At concentrations where the 25-kDa PEI resulted in >95% cell death, the conjugates afforded nearly full cell viability. The cross-linked PEIs were 17 to 80 times more efficient than the unmodified ones in vivo; furthermore, their efficiencies were up to twice that of the 25-kDa PEI. CONCLUSIONS: Cross-linking of small PEIs with judiciously designed amide- and ester-bearing linkers boosts their gene delivery efficiency both in vitro and in vivo without increasing the cytotoxicity. The high efficiency is dependent on the nature of the linkages and the PEIs used.

Animals↗
PubMed2000

Serial CT and MR imaging of carmustine wafers.

BACKGROUND AND PURPOSE: A new option in the treatment of recurrent malignant glioma is surgical placement of chemotherapy-laden biodegradable wafers. We describe the CT and MR appearance of chemotherapy wafers in patients after surgery for recurrent malignant glioma METHODS: Eighteen patients had carmustine (BCNU) wafers implanted during reoperation for malignant glioma; three patients had empty, placebo wafers placed. The 21 patients had a total of 22 CT and 57 MR imaging studies. Repeat CT studies were conducted for up to 6 months, the MR studies for up to 1 year. Examinations were evaluated for attenuation on CT scans, signal abnormalities on MR images, and changing appearance during the follow-up period. Enhancement characteristics were also assessed. RESULTS: On CT scans, 13 of 16 acute (<7 days) cases showed linear high-attenuation wafers, with three showing low attenuation. On MR images, all T1 and T2 studies performed in the acute stage showed decreased signal of the wafers. Eight of 15 studies showed a transient increase in T1 only at about 2 months. Wafers decreased in conspicuity on both CT and MR studies after 2 months. The wafers did not enhance. One postoperative tumor showed a transient increase in edema and increased enhancement at 5 weeks. The presence or absence of BCNU within the wafers did not change their appearance. CONCLUSION: BCNU wafers have a characteristic appearance: in the first 7 days after implantation they are linear, usually of increased attenuation on CT scans, and always show decreased signal on MR images; they do not enhance, and become less conspicuous after 2 months.

Antineoplastic Agents, Alkylating↗
PubMed2006

Encapsulating drugs in biodegradable ultrafine fibers through co-axial electrospinning.

This article describes an electrospinning process to fabricate double-layered ultrafine fibers. A bioabsorbable polymer, Polycaprolactone (PCL), was used as the outer layer or the shell and two medically pure drugs, Resveratrol (RT, a kind of antioxidant) and Gentamycin Sulfate (GS, an antibiotic), were used as the inner layers or the cores. Morphology and microstructure of the ultrafine fibers were characterized by scanning electron microscope (SEM) and transmission electron microscopy (TEM), whereas mechanical performance of them was understood through tensile test. In vitro degradation rates of the nanofibrous membranes were determined by measuring their weight loss when immersed in pH 7.4 phosphate-buffered saline (PBS) mixed with certain amount of Pseudomonas lipase for a maximum of 7 days. The drug release behaviors of the RT and GS were measured using a high performance liquid chromatography (HPLC) and ultraviolet-visible (UV-vis) spectroscopy, respectively. It has been found that the drug solutions without any fiber-forming additive could be encapsulated in the PCL ultrafine fibers, although they alone cannot be made into a fiber form. Beads on the fiber surface influenced the tensile behavior of the ultrafine fibers remarkably. When the core solvent was miscible with the shell solvent, higher drug concentration decreased the bead formation and thus favored the mechanical performance. The situation, however, became different if the two solvents were immiscible with each other. The degradation rate was closely related to hydrophilicity of the drugs in the cores. Higher hydrophilicity apparently led to faster degradation. The release profiles of the RT and GS exhibited a sustained release characteristic, with no burst release phenomenon.

Anti-Bacterial Agents↗
PubMed2006

Effect of nanoparticle size on the extravasation and the photothrombic activity of meso(p-tetracarboxyphenyl)porphyrin.

Particle size should be optimized to achieve targeted and extended drug delivery to the affected tissues. We describe here the effects of the mean particle size on the pharmacokinetics and photothrombic activity of meso-tetra(carboxyphenyl)porphyrin (TCPP), which is encapsulated into biodegradable nanoparticles based on poly(d,l-lactic acid). Four batches of nanoparticles with different mean sizes ranging from 121 to 343 nm, were prepared using the emulsification-diffusion technique. The extravasations of each TCPP-loaded nanoparticle formulation from blood vessels were measured, as well as the extent of photochemically induced vascular occlusion. These preclinical tests were carried out in the chorioallantoic membrane (CAM) of the chicken's embryo. Fluorescence microscopy showed that both the effective leakage of TCPP from the CAM blood vessels and its photothrombic efficiency were dependent on the size of the nanoparticle drug carrier. Indeed, the TCPP fluorescence contrast between the blood vessels and the surrounding tissue increased at the applied conditions, when the particle size decreased. This suggests that large nanoparticles are more rapidly eliminated from the bloodstream. In addition, after injection of a drug dose of 1mg/kg body weight and a drug-light application interval of 1 min, irradiation with a fluence of 10J/cm(2) showed that the extent of vascular damage gradually decreased when the particle size increased. The highest photothrombic efficiency was observed when using the TCPP-loaded nanoparticles batch with a mean diameter of 121 nm. Thus, in this range of applied conditions, for the treatment of for instance a disease like choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD), these experiments suggest that the smallest nanoparticles may be considered as the optimal formulation since they exhibited the greatest extent of vascular thrombosis as well as the lowest extravasation.

Animals↗
PubMedDate not supplied

Polyacetal-doxorubicin conjugates designed for pH-dependent degradation.

Terpolymerization of poly(ethylene glycol) (PEG), divinyl ethers, and serinol can be used to synthesize water soluble, hydrolytically labile, amino-pendent polyacetals (APEGs) suitable for drug conjugation. As these polyacetals display pH-dependent degradation (with faster rates of hydrolysis at acidic pH) and they are not inherently hepatotropic after intravenous (iv) injection, they have potential for development as biodegradable carriers to facilitate improved tumor targeting of anticancer agents. The aim of this study was to synthesize a polyacetal-doxorubicin (APEG-DOX) conjugate, determine its cytotoxicity in vitro and evaluate its potential for improved tumor targeting in vivo compared to an HPMA copolymer-DOX conjugate in clinical development. Amino-pendent polyacetals were prepared, and following succinoylation (APEG-succ), the polymeric intermediate conjugated to DOX via one of three methods using carbodiimide mediated coupling (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in aqueous solution was the most successful). The resultant APEG-DOX conjugates had a DOX content of 3.0-8.5 wt %, contained <1.2% free DOX (relative to total DOX content) and had a M(w) = 60000-100000 g/mol and M(w)/M(n) = 1.7-2.6. In vitro cytotoxicity studies showed APEG-DOX to be 10-fold less toxic toward B16F10 cells than free DOX (IC(50) = 6 microg/mL and 0.6 microg/mL respectively), but confirmed the serinol-succinoyl-DOX liberated during main-chain degradation to be biologically active. When administered iv to C57 black mice bearing subcutaneous (sc) B16F10 melanoma, APEG-DOX of M(w) = 86000 g/mol, and 5.0 wt % DOX content exhibited significantly (p < 0.05) prolonged blood half-life and enhanced tumor accumulation compared to an HPMA copolymer-GFLG-DOX conjugate of M(w) = 30000 g/mol and 6.2 wt % DOX content. Moreover, APEG-DOX exhibited lower uptake by liver and spleen. These observations suggest that APEG anticancer conjugates warrant further development as novel polymer therapeutics for improved tumor targeting.

Acetals↗
PubMed1996

Stabilization of tetanus toxoid in poly(DL-lactic-co-glycolic acid) microspheres for the controlled release of antigen.

Sustained release of antigenically active tetanus toxoid (TT) for several weeks from biodegradable poly (DL-lactic-co-glycolic acid) (PLGA) microspheres is very important for the development of a single dose vaccine. With a view to developing such a formulation, we evaluated in the vitro release of antigenic TT from TT-containing PLGA films and microspheres stabilized with gelatin or human serum albumin. Without stabilizer, TT-containing PLGA films released low levels of antigenic TT whereas TT-containing PLGA microspheres (average size 50 microMs) released 18% of antigenic TT in 4 weeks. Inclusion of gelatin and human serum albumin increased the amount of antigenic TT released from PLGA films and microspheres. As the concentration of gelatin increased from 0.08% to 2.2% in PLGA films, release of antigenic TT also increased. Similar results were found with gelatin-stabilized TT-containing microspheres. But the significant increase by higher concentration of gelatin was on the initial burst during the first week. A concentration of 0.2% gelatin was found suitable for getting approximately 40% of antigenic TT in 4 weeks. The proportion of antigenic TT to total protein was higher during the first 2 weeks of the release studies (50% during the first week and 23% during the second week). After 2 weeks, the proportion of antigenic TT was approximately 10% for the next 2 weeks. TT-containing microspheres stabilized with gelatin and human serum albumin showed stability of antigenic TT release when these microspheres were stored at 37 degrees C for 4 weeks. Gelatin appears to be a good stabilizer for TT-containing microspheres, but further studies are required to increase the proportion of antigenic TT beyond 2 weeks.

Antigens↗
PubMed2002

Enhancement of immune responses by co-delivery of a CpG oligodeoxynucleotide and tetanus toxoid in biodegradable nanospheres.

Synthetic oligodeoxynucleotides (ODN) consisting of unmethylated bacterial DNA sequences with CpG motifs are potent immunological adjuvants. Immunostimulatory CpG sequences are species-specific. Optimal CpG sequences specific for humans, rodents, livestock, and companion animals have been reported. Nearly all of these reports describe the use of soluble forms of CpG ODN and antigens. We investigated the co-delivery of CpG ODN and antigens in biodegradable nanospheres as an alternative approach for immunization using tetanus toxoid (TT) as the model antigen and ODN #1826 as the model CpG sequence. TT and CpG ODN were co-encapsulated in poly(D,L-lactic-co-glycolic acid) nanospheres. Separate groups of C57BL/6 mice were subcutaneously immunized twice with TT and CpG ODN in nanospheres (test group), TT alone in nanospheres, TT alone in nanospheres mixed with CpG ODN in solution, TT and CpG ODN both in solution (reference group), TT alone in solution, and alum adsorbed TT. T cells isolated from the test group showed strong antigen-specific T cell proliferation ex vivo (stimulation index=45). This was significantly (P<0.0001) higher than that observed for T cells isolated from the reference group. The T cell proliferation of the test group was associated with higher levels of interferon gamma secretion (IFN-gamma 2694.7+/-41.1 pg/ml) than that of the reference group (814.7+/-50.2 pg/ml). Interleukin 4 (IL-4) secretion, if any, was below the detection limit (<13 pg/ml) in all the groups. Anti-sera obtained from the test group also showed very high total IgG titers (end point titers, 2560000) that were 16 times higher than the reference group. Similarly, differences of 8-fold for IgG1 and IgG3, and 5-fold for IgG2b titers were observed. Noticeably, the antibody response induced in the alum-TT group was far less (total IgG, end point titers 160000) than that obtained in the TT-CpG ODN nanospheres group. Overall, the results show that co-delivery of CpG and TT resulted in induction of both T helper type 1 and type 2 (Th1 and Th2) immune responses with a bias towards Th1 type. These results suggest that the co-delivery of CpG ODN adjuvants and antigens in nanospheres is a more efficient approach for immunization than the use of CpG ODN and TT in solution.

Adjuvants, Immunologic↗
PubMed2006

Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo.

Targeted uptake of therapeutic nanoparticles in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology. Using prostate cancer as a model, we report docetaxel (Dtxl)-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2'-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate-specific membrane antigen (PSMA), a well characterized antigen expressed on the surface of prostate cancer cells. These Dtxl-encapsulated nanoparticle-aptamer bioconjugates (Dtxl-NP-Apt) bind to the PSMA protein expressed on the surface of LNCaP prostate epithelial cells and get taken up by these cells resulting in significantly enhanced in vitro cellular toxicity as compared with nontargeted nanoparticles that lack the PSMA aptamer (Dtxl-NP) (P < 0.0004). The Dtxl-NP-Apt bioconjugates also exhibit remarkable efficacy and reduced toxicity as measured by mean body weight loss (BWL) in vivo [body weight loss of 7.7 +/- 4% vs. 18 +/- 5% for Dtxl-NP-Apt vs. Dtxl-NP at nadir, respectively (mean +/- SD); n = 7]. After a single intratumoral injection of Dtxl-NP-Apt bioconjugates, complete tumor reduction was observed in five of seven LNCaP xenograft nude mice (initial tumor volume of approximately 300 mm3), and 100% of these animals survived our 109-day study. In contrast, two of seven mice in the Dtxl-NP group had complete tumor reduction with 109-day survivability of only 57%. Dtxl alone had a survivability of only 14%. Saline and nanoparticles without drug were similarly nonefficacious. This report demonstrates the potential utility of nanoparticle-aptamer bioconjugates for a therapeutic application.

Animals↗
PubMed1997

Spherex (degradable starch microspheres) chemo-occlusion--enhancement of tumor drug concentration and therapeutic efficacy: an overview.

The efficacy of systemic chemotherapy in the treatment of primary and secondary liver cancer is poor. Intra-arterial delivery of fluoropyrimidines resulted in a significantly higher tumor response, but survival was prolonged by only a few months. Obviously, there is still a great need for improved therapeutic strategies. As the regional blood flow is of importance for the advantage of intra-arterial administration of cytotoxic drugs, degradable starch microspheres (DSMs) have been developed specifically to achieve temporary vascular occlusion during coadministration of cytotoxic drugs. Peak plasma concentrations, as well as the area under the concentration-time curve (AUC) of mitomycin C in plasma have been found to be significantly reduced following intra-arterial coadministration with DSMs. Similar results were also obtained with other drugs, such as nitrosoureas, doxorubicin, and 5-fluorouracil. The temporary vascular occlusion induced by DSMs enables a coadministered drug to be lodged in the target area for a prolonged period of time, resulting in a selectively increased uptake of labeled low molecular weight markers and several cytotoxic drugs into liver tumors compared with normal liver tissue. Vascular occlusion induced by DSMs has been demonstrated to redistribute the blood flow to hypovascular areas, which might be of particular importance for improving the efficacy of intra-arterial chemotherapy of hypovascular liver tumors. Passage through arteriovenous shunts was generally increased after DSM injection. However, this was without clinical significance as respiratory distress symptoms were found in only 1% of the sessions and were not considered to be serious in any of these patients. To take advantage of the pharmacokinetic modulation of coinjected drugs and, in addition, the redistribution of blood flow to hypovascular tumor areas, the goal is to achieve an almost complete vascular occlusion by injection of DSMs. Therefore, due to the wide variation between patients in the size and vascularity of liver tumors, the dose of DSMs has to be individualized. Degradable starch microspheres have been shown to enhance the antitumor efficacy of several cytotoxic drugs in animal experimental models and in noncomparative and randomized clinical studies.

Animals↗
PubMed2004

IGF-I and TGF-beta 1 incorporated in a poly(D,L-lactide) implant coating maintain their activity over long-term storage-cell culture studies on primary human osteoblast-like cells.

Biodegradable coating of osteosynthetic materials with poly(D,L-lactide) (PDLLA) and incorporated growth factors has been used successfully as drug carrier to stimulate fracture healing in several rat and porcine models. A cold coating technique was used to incorporate growth factors without loss of activity during the coating process. The aim of this study was to investigate the activity of incorporated insulin like growth factor-I and transforming growth factor-beta 1 (TGF-beta1) after long-time storage (5 and 14 months at -20 degrees C). Primary human osteoblast-like cells (HOB) were cultured in a non-contact manner with titanium wires coated with PDLLA and IGF-I (33 microg) and TGF-beta1 (6 microg) for 0, 5, 10 and 15 days. Osteoblast culture without wires, with titanium wires or wires with the PDLLA coating served as control ( n=3 each time point and group). Cell vitality, cell proliferation and the production of procollagen 1 were measured. No differences in cell count and vitality were accessed in the two growth factor treated groups compared to the control groups at the same time point. Independently from the storage duration, the incorporated growth factors significantly stimulated the production of osteoblast specific type I collagen (CICP) compared to the controls. The results indicate, that the growth factors stimulated osteoblast to an enhanced collagen 1 production and that the coating method meets a major requirement for clinical use of growth factor-coated implants: biological activity of the incorporated growth factors for at least 14 months.

Cell Division↗
PubMed2005

Development and characterization of sub-micron poly(D,L-lactide-co-glycolide) particles loaded with magnetite/maghemite nanoparticles.

PURPOSE: The objective of this study is to develop biodegradable sub-micron poly(lactide-co-glycolide) particles loaded with magnetite/maghemite nanoparticles for intravenous drug targeting. METHOD: Sub-micron magnetite/PLGA particles (also called composite nanoparticles) were prepared by a modified double emulsion method (w/o/w) or by an emulsion-evaporation process (o/w). To optimize the composite nanoparticles formulation, the influence of some experimental parameters, such as types of magnetite/maghemite nanoparticles, volume of magnetite suspension and amount of polymer were investigated. The morphology, size and zeta potential of the magnetite/PLGA nanoparticles were determined. The magnetite entrapment efficiency and magnetite content were assessed by dosing iron in the composite nanoparticles. RESULTS: TEM photomicrographs showed that the composite nanoparticles were almost spherical in shape with a rather monomodal distribution in size. All composite nanoparticle formulations were found to have the mean diameter within the range of 268-327 nm with polydispersity index within the range of 0.02-0.15. Magnetite nanoparticles coated with oleic acid showed more efficient entrapment (60%) as compared to uncoated magnetite nanoparticles (48%). In both cases, when the volume of magnetite suspension increased, the magnetite entrapment efficiency decreased but the magnetite content increased. In addition, the two-fold rise in the amount of polymer did not significantly affect the composite nanoparticle characteristics except the magnetite content. Finally, none modification of the mean diameter of the composite nanoparticles was observed after storage for 3 months at 4 degrees C. CONCLUSIONS: Magnetite/PLGA nanoparticles were prepared and the influence of some process parameters have been assessed. Improvement of the magnetite entrapment efficiency are in progress and the magnetization properties of the composite nanoparticles will subsequently be tested.

Adsorption↗
PubMedDate not supplied

Polycefin, a new prototype of a multifunctional nanoconjugate based on poly(beta-L-malic acid) for drug delivery.

A new prototype of nanoconjugate, Polycefin, was synthesized for targeted delivery of antisense oligonucleotides and monoclonal antibodies to brain tumors. The macromolecular carrier contains: 1. biodegradable, nonimmunogenic, nontoxic beta-poly(L-malic acid) of microbial origin; 2. Morpholino antisense oligonucleotides targeting laminin alpha4 and beta1 chains of laminin-8, which is specifically overexpressed in glial brain tumors; 3. monoclonal anti-transferrin receptor antibody for specific tissue targeting; 4. oligonucleotide releasing disulfide units; 5. L-valine containing, pH-sensitive membrane disrupting unit(s), 6. protective poly(ethylene glycol); 7. a fluorescent dye (optional). Highly purified modules were conjugated directly with N-hydroxysuccinimidyl ester-activated beta-poly(L-malic acid) at pendant carboxyl groups or at thiol containing spacers via thioether and disulfide bonds. Products were chemically validated by physical, chemical, and functional tests. In vitro experiments using two human glioma cell lines U87MG and T98G demonstrated that Polycefin was delivered into the tumor cells by a receptor-mediated endocytosis mechanism and was able to inhibit the synthesis of laminin-8 alpha4 and beta1 chains at the same time. Inhibition of laminin-8 expression was in agreement with the designed endosomal membrane disruption and drug releasing activity. In vivo imaging showed the accumulation of intravenously injected Polycefin in brain tumor tissue via the antibody-targeted transferrin receptor-mediated endosomal pathway in addition to a less efficient mechanism known for high molecular mass biopolymers as enhanced permeability and retention effect. Polycefin was nontoxic to normal and tumor astrocytes in a wide range of concentrations, accumulated in brain tumor, and could be used for specific targeting of several biomarkers simultaneously.

Animals↗
PubMed2004

Mechanistic evaluation of the glucose-induced reduction in initial burst release of octreotide acetate from poly(D,L-lactide-co-glycolide) microspheres.

One major obstacle for development of injectable biodegradable microspheres for controlled peptide and protein delivery is the high initial burst of drug release occurring over the first day of incubation. We describe here the significant reduction in initial burst release of a highly water-soluble model peptide, octreotide acetate, from poly(D,L-lactide-co-glycolide) microspheres by the co-encapsulation of a small amount of glucose (e.g., 0.2%w/w), i.e., from 30+/-20% burst - glucose to 8+/-3% + glucose (mean+/-SD, n=4). This reduction is unexpected since hydrophilic additives are known to increase porosity of microspheres, causing an increase in permeability to mass transport and a higher burst. Using the double emulsion-solvent evaporation method of encapsulation, the effect of glucose on initial burst in an acetate buffer pH 4 was found to depend on polymer concentration, discontinuous phase/continuous phase ratio, and glucose content. Extensive characterization studies were performed on two microsphere batches, +/-0.2% glucose, to elucidate the mechanism of this effect. However, no significant difference was observed with respect to specific surface area, porosity, internal and external morphology and drug distribution. Continuous monitoring of the first 24-h release of octreotide acetate from these two batches disclosed that even though their starting release rates were close, the microspheres + glucose exhibited a much lower release rate between 0.2 and 24h compared to those - glucose. The microspheres + glucose showed a denser periphery and a reduced water uptake at the end of 24-h release, indicating decreased permeability. However, this effect at times was offset as glucose content was further increased to 1%, causing an increase in surface area and porosity. In summary, we conclude that the effect of glucose on initial burst are determined by two factors: (1) increased initial burst due to increased osmotic pressure during encapsulation and drug release, and (2) decreased initial burst due to decreased permeability of microspheres.

Coated Materials, Biocompatible↗
PubMed2004

Pharmacokinetic and immunosuppressive effects of tacrolimus-loaded biodegradable microspheres.

The objective of this study was to characterize the pharmacokinetics and immunosuppression of a tacrolimus-loaded biodegradable microsphere (TLBM) in rats. We prepared TLBM. DA/Slc rats were given TLBM at a dose of 1.6 mg/kg (n = 9), 2.4 mg/kg (n = 5), or 7.2 mg/kg (n = 7) tacrolimus contents by a single subcutaneous administration to achieve sustained release over a long period. DA/Slc rats were given TLBM by a single subcutaneous administration at a dose of 4.8 mg/kg (n = 6) tacrolimus contents to clarify the main site of TLBM uptake in the organs. In the rat liver transplantation model, the recipients were given TLBM at a dose of 0.16 mg/kg (n = 5), 2.4 mg/kg (n = 4), or 4.8 mg/kg (n = 5) tacrolimus contents by a single subcutaneous administration on the first day after operation. Overall survival days were compared. Continuous flat parallel concentration profiles were significant for 10 days from the first day after a single subcutaneous administration of TLBM (P <.01). The relationship between the dosages of TLBM administration and area under the concentration-time curve (AUC) up to 18 days demonstrated a linear regression line (P <.01). In addition, the relationship between the dose of TLBM and the survival days of the recipients in the liver transplantation model showed a positive correlation. The current pharmacokinetic study of TLBM revealed significantly increased tacrolimus levels in the regional lymph nodes compared with other organs except bone marrow (P <.01). In conclusion, TLBM allowed tacrolimus to release gradually in a very stable manner for 10 days, with dose-dependent immunosuppression after a single subcutaneous administration. The main site of TLBM uptake after subcutaneous administration was the regional lymph node of administration site.

Animals↗
PubMed1995

Response to intracrevicular controlled delivery of 25% tetracycline from poly(lactide/glycolide) film strips in SPT patients.

Controlled local delivery of antibiotics has been shown to reduce periodontopathic micro-organisms with minimal side-effects. Clinical studies in our laboratory have shown that 25% tetracycline HCl delivered from poly(D,L-lactide/glycolide) film strips (25 TTC-PLGA) released therapeutic concentrations of tetracycline for 10 days. The present pilot study compared the intracrevicular delivery of 25% tetracycline HCl incorporated in these biodegradable film strips to scaling and root planing (SRP) in 10 adult periodontitis patients, who in spite of therapy and regular supportive periodontal treatment (SPT), continued to possess 5 bleeding periodontal pockets at least 5 mm deep. Sites were randomly selected to receive the following treatments: (1) 25 TTC-PLGA, (2) control strips without TTC (PLGA), (3) SRP, and (4) untreated control. Film-strip retention was augmented with a suture/cement technique, followed by strip removal after 2 weeks. Clinical parameters and subgingival bacterial morphotypes (darkfield analysis) were evaluated over time (0, 2.4, 8, 12, 26 weeks). Results indicated that, compared to baseline, 25 TTC-PLGA film strips caused significant (p < or = 0.01): (1) probing depth reduction for 26 weeks, (2) a clinical attachment level gain for 12 weeks, (3) lower %s of spirochetes for 4 weeks and motile rods for 8 weeks (p < or = 0.05), and (4) an accompanying increase in cocci for 4 weeks. In the scaled and root planed sites, probing depth was the only finding that demonstrated a significant change from baseline (p < or = 0.01). Controls and PLGA showed isolated reductions in probing depth and % of motile organisms. From these findings, applications of intracrevicular 25 TTC-PLGA, when compared to scaling and root planing, appears to have an enhanced antibacterial effect and a similar clinical effect in SPT patients. The results of this study indicate further investigation of 25 TTC-PLGA film strips should be undertaken using more subjects and sophisticated microbiological and clinical measurements.

Adult↗
PubMed2000

Controlled release of transforming growth factor beta1 from biodegradable polymer microparticles.

Recombinant human transforming growth factor beta1 (TGF-beta1) was incorporated into biodegradable microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) at 6 ng/1 mg microparticles. Fluorescein isothiocynate labeled bovine serum albumin (FITC-BSA) was coencapsulated as a porogen at 4 microg/1 mg of microparticles. The effects of PEG content (0, 1, or 5 wt %) and buffer pH (3, 5, or 7.4) on the protein release kinetics and the degradation of PLGA were determined in vitro for up to 28 days. The entrapment yield of TGF-beta1 was 83.4 +/- 13.1 and 54.2 +/- 12.1% for PEG contents of 0 and 5%, respectively. The FITC-BSA and TGF-beta1 were both released in a multiphasic fashion including an initial burst effect. Increasing the PEG content resulted in the decreased cumulative mass of released proteins. By day 28, 3.8 +/- 0. 1 and 2.8 +/- 0.3 microg (based on 1 mg microparticles) of loaded FITC-BSA and 3.4 +/- 0.2 and 2.2 +/- 0.3 ng of loaded TGF-beta1 were released into pH 7.4 phosphate buffered saline (PBS) from microparticles with 0 and 5% PEG, respectively. Aggregation of FITC-BSA occurred at lower buffer pH, which led to decreased release rates of both proteins. For microparticles with 5% PEG, 2.3 +/- 0.1 microg of FITC-BSA and 2.0 +/- 0.2 ng of TGF-beta1 were released in pH 7.4 buffer after 28 days, while only 1.7 +/- 0.3 microg and 1.3 +/- 0.4 ng of the corresponding proteins were released in pH 3 buffer. The degradation of PLGA was also enhanced at 5% PEG content, which was significantly accelerated at acidic pH conditions. The calculated half-lives of PLGA were 20.3 +/- 0.9 and 15.9 +/- 1.2 days for PEG contents of 0 and 5%, respectively, in pH 7.4 PBS and 14.8 +/- 0.4 and 5.5 +/- 0.1 days for 5% PEG in pH 7.4 and 3 buffers, respectively. These results suggest that PLGA/PEG blend microparticles are useful as delivery vehicles for controlled release of growth factors.

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