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PubMed2004

Chitosan-DNA nanoparticles as non-viral vectors in gene therapy: strategies to improve transfection efficacy.

Currently, the major drawback of gene therapy is the gene transfection rate. The two main types of vectors that are used in gene therapy are based on viral or non-viral gene delivery systems. The viral gene delivery system shows a high transfection yield but it has many disadvantages, such as oncogenic effects and immunogenicity. However, cationic polymers, like chitosan, have potential for DNA complexation and may be useful as non-viral vectors for gene therapy applications. Chitosan is a natural non-toxic polysaccharide, it is biodegradable and biocompatible, and protects DNA against DNase degradation and leads to its condensation. The objective of this paper was to summarize the state of the art in gene therapy and particularly the use of chitosan to improve the transfection efficiency in vivo and in vitro.

Chitosan↗
PubMedDate not supplied

Caprolactonic poloxamer analog: PEG-PCL-PEG.

The aqueous solution of poly(ethylene glycol)-poly(caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG) triblock copolymers (> 15. wt. %) undergoing "clear sol-gel-turbid sol" transition as the temperature increases from 20 to 60 degrees C has been developed. Light scattering and 13C NMR study suggested that the transition mechanisms are the micellar aggregation for the clear sol to gel transition (lower transition), whereas the increase in PCL molecular motion for gel to turbid sol transition (upper transition). In contrast to the previous thermogelling biodegradable polymers with a sticky paste morphology, the powder form of the PEG-PCL-PEG triblock copolymers makes it easy to handle and allows fast dissolution in water. Therefore, the lyophilization into a powder form followed by facile reconstitution was possible. This system is believed to be promising for drug delivery, cell therapy, and tissue engineering.

Biocompatible Materials↗
PubMed1998

Pharmaceutical applications of in vivo EPR.

The aim of this article is to discuss the applications of in vivo EPR in the field of pharmacy. In addition to direct detection of free radical metabolites and measurement of oxygen, EPR can be used to characterize the mechanisms of drug release from biodegradable polymers. Unique information about drug concentration, the microenvironment (viscosity, polarity, pH) and biodistribution (by localized measurement or EPR Imaging) can be obtained.

Animals↗
PubMed2000

O6-benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma.

Local delivery of carmustine (BCNU) via biodegradable polymers prolongs survival against experimental brain tumors and in human clinical trials. O6-benzylguanine (O6-BG), a potent inhibitor of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), has been shown to reduce nitrosourea resistance and, thus, enhance the efficacy of systemic BCNU therapy in a variety of tumor models. In this report, we demonstrate that O6-BG can potentiate the activity of BCNU delivered intracranially via polymers in rats challenged with a lethal brain tumor. Fischer 344 rats received a lethal intracranial challenge of 100,000 F98 glioma cells (F98 cells have significant AGT activity, 328 fmol/mg protein). Five days later, animals receiving an i.p. injection of O6-BG (50 mg/kg) 2 h prior to BCNU polymer (3.8% BCNU by weight) implantation had significantly improved survival (n = 7; median survival, 34 days) over animals receiving either O6-BG alone (n = 7; median survival, 22 days; P = 0.0002) or BCNU polymer alone (n = 8; median survival, 25 days; P = 0.0001). Median survival for the control group (n = 8) was 23.5 days. Moreover, there was no physical, behavioral, or pathological evidence of treatment-related toxicity. These findings suggest that O6-BG can potentiate the effects of interstitially delivered BCNU and, for tumors expressing significant AGT, may be necessary for the BCNU to provide a meaningful therapeutic benefit. Given the clinical use of BCNU polymers against malignant gliomas, concurrent treatment with O6-BG may provide an important addition to our therapeutic armamentarium.

Animals↗
PubMed1999

Biodegradable recombinant human erythropoietin loaded microspheres prepared from linear and star-branched block copolymers: influence of encapsulation technique and polymer composition on particle characteristics.

Recombinant human erythropoietin (EPO) and fluorescein isothiocyanate labeled dextran (FITC-dextran) loaded microspheres were prepared by a modified W/O/W double-emulsion technique. Biodegradable linear ABA block copolymers consisting of poly(L-lactide-co-glycolide) A blocks attached to central poly(ethyleneoxide) (PEO) B blocks and star-branched AB block copolymers containing A blocks of poly(L-lactide) or poly(L-lactide-co-glycolide) and star-branched poly(ethyleneoxide) B blocks were investigated for their potential as sustained release drug delivery systems. Microsphere characteristics were strongly influenced by the polymer composition. In the case of the linear block copolymers, a reduced lactic acid content in a linear block copolymer yielded smaller particles, a lower encapsulation efficiency, and a higher initial drug release both in the case of EPO and FITC-dextran. The investigation of the effects of several manufacturing parameters on microsphere formation showed that the process temperature plays an important role. Microsphere formation in a +1 degrees C environment resulted in higher drug loadings without increasing the amount of residual dichloromethane inside the particles. Other parameters such as the homogenization of the primary W/O emulsion and of the W/O/W double-emulsion have less impact on microsphere characteristics. Branched block copolymers containing star-shaped PEO also showed potential for the preparation of drug loaded microspheres. A certain amount of glycolic acid in the copolymer was necessary for the successful preparation of non-aggregating microspheres at room temperature. Again, the processing temperature strongly affected particle characteristics. Microsphere preparation at +1 degrees C allows the formation of microspheres from a polymer not containing glycolic acid, a result which could not be achieved at room temperature. Moreover, compared to microsphere formation at room temperature, the effective FITC-dextran loading was increased. Concerning the EPO loaded microspheres, the amount of EPO aggregated was comparable to that using the linear ABA polymers. A continuous release of the protein from these star-shaped polymers could not be achieved. In conclusion, apart from microsphere preparation in a +1 degrees C environment the choice of the polymer represents the main factor for a successful entrapment of proteins into biodegradable microspheres.

Biodegradation, Environmental↗
PubMed2000

Nonionic Cellulose Ethers as Potential Drug Delivery Systems for Periodontal Anesthesia.

Nonionic cellulose ethers displaying a lower consolute temperature, or cloud-point, close to body temperature were investigated as potential carrier systems for the delivery of local anesthetic agents to the periodontal pocket. The interaction between the polymers, i.e., ethyl(hydroxyethyl)cellulose (EHEC) and hydrophobically modified EHEC (HM-EHEC), and ionic surfactants was determined in the absence and in the presence of the local anesthetic agents lidocaine and prilocaine. The cloud-point and rheology data indicate interactions between the polymer and both anionic and cationic surfactants. More precisely, a number of ionic surfactants were found to result in an increase in cloud-point at higher surfactant concentrations, a surfactant-concentration-dependent thickening, and a temperature-induced gelation upon heating. Upon addition of the local anesthetic agents lidocaine and prilocaine in their uncharged form to EHEC and HM-EHEC, in the absence of surfactants, only minor interaction with the polymer could be inferred. However, these substances were found to affect the polymer-surfactant interaction. In particular, the drug release rate in vitro as well as the stability and temperature-dependent viscosity were followed for an EHEC/SDS system and EHEC/myristoylcholine bromide system upon addition of lidocaine and prilocaine. The data indicate a possibility of formulating a local anesthetic drug delivery system suitable for administration into the periodontal pocket where at least small amounts of active ingredients can be incorporated into the system without severely affecting the gelation behavior. The results found for the cationic myristoylcholine bromide system are particularly interesting for the application in focus here since this surfactant is antibacterial and readily biodegradable. Copyright 2000 Academic Press.

Journal Article↗
PubMed2004

In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery.

The aim of the present work was to assess the merits of an actively targetable nanoparticles (ATN), PEG-coated biodegradable polycyanoacrylate nanoparticles (PEG-nanoparticles) conjugated to transferrin, for paclitaxel delivery. PEG-nanoparticles loading paclitaxel were prepared by solvent evaporation technique in advance. ATN were prepared by coupling of transferrin to PEG-nanoparticles. The results showed that the average encapsulation efficiency of ATN was 93.4+/-3.6% with particle size (101.4+/-7.2 nm) and zeta-potential (-13.6+/-1.1 mV). The paclitaxel loaded ATN exhibited a low burst effect with about only 16.2% drug release within the first phase. Subsequently, paclitaxel release profiles displayed a sustained release phase. The amount of cumulated paclitaxel release over 30 days was 81.6%. ATN exhibited a markedly delayed blood clearance in mice, and the paclitaxel level from ATN remained much higher at 24 h compared with that of free drug from paclitaxel injection. The distribution profiles of ATN in S-180 solid tumor-bearing mice after intravenous administration showed the tumor accumulation of paclitaxel increase with time, and the paclitaxel concentration in tumor was about 4.8 and 2.1 times higher than those from paclitaxel injection and PEG-nanoparticles at 6 h after intravenous injection. For mice treated with 20 mg/kg x 5 of ATN, the decrease in body weight was limited within 4% of the initial weight at 5 days after the final administration, and tumor regression was significantly observed with complete tumor regression for five out of nine mice. The tumor burden with ATN-treated mice was much smaller compared with free paclitaxel or NTN-treated mice. In addition, the life span of tumor-bearing mice was significantly increased when they were treated with ATN, in particular, three mice survived over 60 days. Thus, PEG-coated biodegradable polycyanoacrylate nanoparticles conjugated to transferrin could be an effective carrier for paclitaxel delivery.

Animals↗
PubMed1999

Radiosensitization of a mouse tumor model by sustained intra-tumoral release of etanidazole and tirapazamine using a biodegradable polymer implant device.

BACKGROUND AND PURPOSE: Drug toxicities are often a limiting factor in long term treatment regimes used in conjunction with radiotherapy. If the drug could be localized to the tumor site and released slowly, then optimal, intra-tumoral drug concentrations could be achieved without the cumulative toxicity associated with repeated systemic drug dosage. In this paper we describe the use of a biodegradable polymer implant for sustained intra-tumoral release of high concentrations of drugs targeting hypoxic cells. MATERIALS AND METHODS: The RIF-1 tumor was implanted subcutaneously or intramuscularly in C3H mice and irradiated with 60Co gamma rays. The drug delivery device was the co-polymer CPP-SA;20:80 into which the drug was homogeneously incorporated. The hypoxic radiosensitizer Etanidazole or the bioreductive drug Tirapazamine were delivered intra-tumorally by means of implanted polymer rods containing the drugs. Tumor growth delay (TGD) was used as the end point in these experiments. RESULTS: Both Etanidazole and Tirapazamine potentiated the effects of acute and fractionated radiation in the intra-muscular tumors but neither drug was effective in sub-cutaneous tumors. Since both drugs target hypoxic cells we hypothesized that the lack of effect in the subcutaneous tumor was attributable to the smaller size of the hypoxic fraction in this tumor model. This was confirmed using the hypoxia marker EF5. CONCLUSIONS: These results indicate that the biodegradable polymer implant is an effective vehicle for the intra-tumoral delivery of Etanidazole and Tirapazamine and that, in conjunction with radiation, this approach could improve treatment outcome in tumors which contain a sub-population of hypoxic, radioresistant cells.

Animals↗
PubMedDate not supplied

The road to bioabsorbable stents: reaching clinical reality?

This article provides an overview of the evolution of revascularization devices since Grüntzig's initial introduction of balloon angioplasty in 1977. In-stent restenosis (ISR) is the major shortcoming of conventional (permanent-implant) stent therapy; even with the innovation and promising benefits of drug-eluting stents, management of ISR is very difficult. ISR is mainly caused by the interaction between the blood and the stent surface and a permanent mechanical irritation of the vascular tissue. Thus stenting technology has moved toward the development of temporary implants composed of biocompatible materials which mechanically support the vessel during the period of high risk for recoil and then completely biodegrade in the long term. Preclinical and first clinical experiences with bioabsorbable magnesium stents are discussed.

Absorbable Implants↗
PubMed2003

Dexamethasone-releasing biodegradable polymer scaffolds fabricated by a gas-foaming/salt-leaching method.

Dexamethasone, a steroidal anti-inflammatory drug, was incorporated into porous biodegradable polymer scaffolds for sustained release. The slowly released dexamethasone from the degrading scaffolds was hypothesized to locally modulate the proliferation and differentiation of various cells. Dexamethasone containing porous poly(D,L-lactic-co-glycolic acid) (PLGA) scaffolds were fabricated by a gas-foaming/salt-leaching method. Dexamethasone was loaded within the polymer phase of the PLGA scaffold in a molecularly dissolved state. The loading efficiency of dexamethasone varied from 57% to 65% depending on the initial loading amount. Dexamethasone was slowly released out in a controlled manner for over 30 days without showing an initial burst release. Release amount and duration could be adjusted by controlling the initial loading amount within the scaffolds. Released dexamethasone from the scaffolds drastically suppressed the proliferations of lymphocytes and smooth muscle cells in vitro. This study suggests that dexamethasone-releasing PLGA scaffolds could be potentially used either as an anti-inflammatory porous prosthetic device or as a temporal biodegradable stent for reducing intimal hyperplasia in restenosis.

Absorbable Implants↗
PubMed2006

PLGA microcapsules with novel dimpled surfaces for pulmonary delivery of DNA.

We describe the fabrication of DNA-loaded poly(lactic-co-glycolic acid) (PLGA) microcapsules with novel surface morphologies that will be of use in pulmonary delivery. Our approach was to examine surface morphology and DNA encapsulation efficiency as a function of primary emulsion stability; using two surfactant series based on hydrophile-lipophile balance and hydrophobe molecular weight. Hydrophilic non-ionic surfactants yielded the most stable water-in-dichloromethane emulsions (HLB values >8). These surfactants normally favor convex (o/w) interfacial curvatures and therefore this atypical behavior suggested a relatively high surfactant solvation in the dichloromethane 'oil' phase. This was consistent with the large fall in the glass transition temperature for microspheres prepared with Tween 20, which therefore efficiently penetrated the PLGA matrix and acted as a plasiticizer. Blends of Pluronic triblock copolymers performed poorly as water-in-dichloromethane emulsifiers, and were therefore used to generate hollow microspheres ('microcapsules') with low densities (0.24 g/cm(3)). Although the Pluronic-stabilized emulsions resulted in lower DNA loading (15-28%), microspheres (approximately 8 microm) with novel dimpled surfaces were fabricated. The depth and definition of the dimples was greatest for triblock copolymers with high MW hydrophobe blocks. By cascade impaction, the geometric mean weight diameter of the microcapsules was 3.43 microm, suggesting that they will be of interest as biodegradable pulmonary delivery vehicles.

Aerosols↗
PubMed2006

Low molecular weight polyethylenimines linked by beta-cyclodextrin for gene transfer into the nervous system.

BACKGROUND: Polyethylenimines (PEIs) with high molecular weights are effective nonviral gene delivery vectors. However, the in vivo use of these PEIs can be hampered by their cellular toxicity. In the present study we developed and tested a new PEI polymer synthesized by linking less toxic, low molecular weight (MW) PEIs with a commonly used, biocompatible drug carrier, beta-cyclodextrin (CyD). METHODS AND RESULTS: The terminal CyD hydroxyl groups were activated by 1,1'-carbonyldiimidazole. Each activated CyD then linked two branched PEI molecules with MW of 600 Da to form a CyD-containing polymer with MW of 61 kDa, in which CyD served as a part of the backbone. The PEI-CyD polymer developed was soluble in water and biodegradable. In cell viability assays with sensitive neurons, the polymer performed similarly to low-MW PEIs and displayed much lower cellular cytotoxicity compared to PEI 25 kDa. The gene delivery efficiency of the polymer was comparable to, and at higher polymer/DNA ratios even higher than, that offered by PEI 25 kDa in neural cells. Attractively, intrathecal injection of plasmid DNA complexed by the polymer into the rat spinal cord provided levels of gene expression close to that offered by PEI 25 kDa. CONCLUSIONS: The polymer reported in the current study displayed improved biocompatibility over non-degradable PEI 25 kDa and mediated gene transfection in cultured neurons and in the central nervous system effectively. The new polymer would be worth exploring further as an in vivo delivery system of therapeutic genetic materials for gene therapy of neurological disorders.

Animals↗
PubMed2000

Biodegradable microparticles with different release profiles: effect on the immune response after a single administration via intranasal and intramuscular routes.

In the development of single-dose microparticulate vaccines, identification of the type of protein release profile required to elicit high and sustainable immune responses is important. Microparticles exhibiting different protein release profiles (continuous, pulsatile and plateau) were made by solvent evaporation or solvent extraction methods from biodegradable polymers encapsulating the model antigen, bovine serum albumin (BSA). The immune responses obtained after a single intranasal or intramuscular administration of microparticles were determined, and also after a subcutaneous boost after 11 months. Microparticles were manufactured with acceptable protein loading and average volume size ranging from 1 to 10 microm. The integrity of BSA extracted and released from microparticles after 2 months incubation was retained. Microparticulate preparations administered by either intranasal or intramuscular routes, evoked rapid, high titre and long-lived (up to 11 months after priming) specific serum IgG responses which were significantly greater than for free BSA. The type of protein release from microparticles had no significant effect on the systemic immune responses. Interestingly, a formulation exhibiting a plateau-release profile was the only microparticulate system capable of inducing significantly greater IgA responses than free BSA after intranasal immunization. This study shows the benefit of microencapsulation in inducing high and long-lasting systemic immune responses after a single dose by both parenteral and mucosal delivery. We conclude that of the microparticles tested, the longevity and magnitude of humoral responses was not effected by the type of in-vitro protein release profile.

Administration, Intranasal↗
PubMed2001

Two-phase partitioning bioreactors in fermentation technology.

The two-phase partitioning bioreactor concept appears to have a great potential in enhancing the productivity of many bioprocesses. The proper selection of an organic solvent is the key to successful application of this approach in industrial practice. The integration of fermentation and a primary product separation step has a positive impact on the productivity of many fermentation processes. The controlled substrate delivery from the organic to the aqueous phase opens a new area of application of this strategy to biodegradation of xenobiotics. In this review, the most recent advances in the application of two-liquid phase partitioning bioreactors for product or substrate partitioning are discussed. Modeling and performance optimization studies related to those bioreactor systems are also reviewed.

Journal Article↗
PubMed2006

In-situ formation of biodegradable hydrogels by stereocomplexation of PEG-(PLLA)8 and PEG-(PDLA)8 star block copolymers.

Eight-arm poly(ethylene glycol)-poly(L-lactide), PEG-(PLLA)(8), and poly(ethylene glycol)-poly(D-lactide), PEG-(PDLA)(8), star block copolymers were synthesized by ring-opening polymerization of either L-lactide or D-lactide at room temperature in the presence of a single-site ethylzinc complex and 8-arm PEG (M(n) = 21.8 x 10(3) or 43.5 x 10(3)) as a catalyst and initiator, respectively. High lactide conversions (>95%) and well-defined copolymers with PLLA or PDLA blocks of the desired molecular weights were obtained. Star block copolymers were water-soluble when the number of lactyl units per poly(lactide) (PLA) block did not exceed 14 and 17 for PEG21800-(PLA)(8) and PEG43500-(PLA)(8), respectively. PEG-(PLA)(8) stereocomplexed hydrogels were prepared by mixing aqueous solutions with equimolar amounts of PEG-(PLLA)(8) and PEG-(PDLA)(8) in a polymer concentration range of 5-25 w/v % for PEG21800-(PLA)(8) star block copolymers and of 6-8 w/v % for PEG43500-(PLA)(8) star block copolymers. The gelation is driven by stereocomplexation of the PLLA and PDLA blocks, as confirmed by wide-angle X-ray scattering experiments. The stereocomplexed hydrogels were stable in a range from 10 to 70 degrees C, depending on their aqueous concentration and the PLA block length. Stereocomplexed hydrogels at 10 w/v % polymer concentration showed larger hydrophilic and hydrophobic domains as compared to 10 w/v % single enantiomer solutions, as determined by cryo-TEM. Correspondingly, dynamic light scattering showed that 1 w/v % solutions containing both PEG-(PLLA)(8) and PEG-(PDLA)(8) have larger "micelles" as compared to 1 w/v % single enantiomer solutions. With increasing polymer concentration and PLLA and PDLA block length, the storage modulus of the stereocomplexed hydrogels increases and the gelation time decreases. Stereocomplexed hydrogels with high storage moduli (up to 14 kPa) could be obtained at 37 degrees C in PBS. These stereocomplexed hydrogels are promising for use in biomedical applications, including drug delivery and tissue engineering, because they are biodegradable and the in-situ formation allows for easy immobilization of drugs and cells.

Biocompatible Materials↗
PubMed2006

In vitro characteristics of poly(lactic-co-glycolic acid) microspheres incorporating gelatin particles loading basic fibroblast growth factor.

AIM: To construct a sustained drug release system for basic fibroblast growth factor (bFGF). With this special system, bFGF can be used to repair an injured peripheral nerve, injured spinal cord, or as a carrier for other drugs that need to be released over a long time. METHODS: Microsphere composite was prepared by encapsulating bFGF into gelatin particles with poly(lactic-co-glycolic acid) (PLGA) as its outer-coating. The encapsulation was conducted by a phase separation method. RESULTS: The average diameter of the gelatin particle-PLGA microsphere composite was 5-18 mum, and bFGF-loading efficiency was up to 80.5%. The bFGF releasing experiment indicated that this new composite system could release bFGF continuously and protect bFGF from denaturation. CONCLUSION: A modified approach was successfully employed to develop a biodegradable system for sustained release of the drug of bFGF in vitro.

Delayed-Action Preparations↗
PubMed1997

In vivo characterization of sustained-release formulations of human growth hormone.

Long-acting formulations of recombinant human growth hormone (rhGH) were prepared by stabilizing and encapsulating the protein into three different injectable, biodegradable microsphere formulations composed of polymers of lactic and glycolic acid. The formulations were compared in juvenile rhesus monkeys by measuring the serum levels of rhGH and two proteins induced by hGH, insulin-like growth factor-I and IGF binding protein-3 (IGFBP-3) after single s.c. administration. All three formulations, which differed principally in the composition of the polymer, provided sustained elevated levels of all three proteins for several weeks, and the rate of release of rhGH differed among the formulations consistent with the molecular weight of the polymer used. All three formulations induced a higher level of insulin-like growth factor-I and insulin-like growth factor binding protein than was induced by daily injections of the same amount of rhGH in solution. After three monthly injections of one of the formulations, both the rhGH and IGF-I levels remained elevated for nearly 90 days. Immunogenicity of the rhGH released from this formulation, as assessed by the incidence of seroconversion to hGH and the titer of anti-hGH antibody in both the rhesus monkeys and transgenic mice expressing rhGH, was no greater than that of the unencapsulated protein. In addition, the microsphere injection sites appeared normal by macroscopic evaluation between 1 to 2 mo after microsphere administration and by microscopic evaluation between 2 to 3 mo. These results show that serum levels of a therapeutic protein can be sustained for an extended period when encapsulated into different formulations of injectable, biodegradable microspheres.

Animals↗
PubMed1993

Engineering of alkyl- and haloaromatic-responsive gene expression with mini-transposons containing regulated promoters of biodegradative pathways of Pseudomonas.

Four recombinant mini-Tn5 transposons are described which contain outward-facing Pm, Pu or Psal promoters from the catabolic plasmids TOL and NAH of Pseudomonas putida, along with their cognate wild-type regulatory genes (xylS, xylR, nahR) or mutant varieties (xylS2). Transcription from such promoters is activated when the host bacteria encounters certain aromatic compounds, such as alkyl- and halobenzoates (XylS, XylS2), alkyl- and halotoluenes (XylR) or salicylates (NahR). These transposons enable the generation of conditional phenotypes dependent on the presence of specific effectors, as well as the engineering of strains expressing heterologous genes that are regulated by aromatic inducers. A mini-Tn5 xylS/Pm::luxAB, was used to construct Pseudomonas strains emitting light upon exposure to concentrations of m-toluate as low as 5-10 microM. The broad-host-range transposition system of Tn5 and the stability of the inserted genes due to the loss of the transposase-encoding gene during delivery of the mobile element make these transposons particularly well suited for the construction of stable strains exhibiting halo/alkyl aromatic-regulated conditional phenotypes in the absence of antibiotic selection, as is required for some uncontained bioremediation and biomonitoring applications.

Benzoates↗