SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
In this overview, novel approaches are described for the controlled release and/or for the targeted delivery of macromolecules such as proteins and DNA. The building stones of these highly complex systems are (phospho)lipids and/or (biodegradable) polymers. They should be carefully chosen and preparation protocols should be rationally designed to maximize chances for success.
PURPOSE: This study was to evaluate the antitumor efficacy of implantable sustained Pingyangmycin (PYM) release system as a polymer based biocompatible implant administrated interstitially in tumors on tumor-bearing nude mice. METHODS: 20 tumor-bearing nude mice established with Tca8113 cell line were divided into five groups .Interstitial chemotherapy (polymer rod each containing 0.1mg PYM was inserted into tumors through puncture needle with internal piston)was performed in mice of Group A, intravenous injection of PYM was made in mice of Group B, intratumoral injection of PYM was given in mice of Group C, polymer rod without PYM was inserted into tumors in Group D and normal saline was intravenously injected in mice of Group E as control. Same total dosage of PYM was given in Group A , B and C. Inhibition rate (IR) based on tumor measurement, apoptosis index (AI) of tumor cells based on TUNEL, apoptosis rate (AT) of tumor cells determined by flow cytometry and histopathological appearances were evaluated and analyzed in different groups. F test was used for statistical analysis by SAS 6.2 software package. RESULTS: The results showed that RI,AT and AI in experimental group (Group A) was significantly higher than that in other groups (P<0.05) Histopathologically, the proliferation of the tumor cells was relatively suppressed in Group A. CONCLUSIONS: Biodegradable PYM-polymer implant may be an optimistic form of drug delivery system in clinic and interstitial chemotherapy is especially suitable for tumors in oral-maxillofacial regions because of easy administration of the implant into the relatively superficial tumors in the regions.
Lactic/glycolic acid polymers (PLGA) are widely used for drug delivery systems. The microsphere formulation is the most interesting dosage form of the PLGA-based controlled release devices. In this study, the previously reported PLGA were used to prepare drug-containing microspheres. Progesterone was used as a model drug. The progesterone microspheres were prepared from PLGA having varied compositions and varied molecular weight. The microscopic characterization shows that the microspheres are spherical, nonaggregated particles. The progesterone-containing PLGA microspheres possess a Gaussian size distribution, having average size from 70-134 microm. A solvent extraction method was employed to prepare the microspheres. The microencapsulation method used in this study has high drug encapsulation efficiency. The progesterone release from the PLGA microspheres and the factors affecting the drug release were studied. The release of progesterone from the PLGA microspheres is affected by the properties of the polymer used. The drug release is more rapid from the microspheres prepared using the PLGA having higher fraction of glycolic acid moiety. The drug release from the microspheres composed of higher molecular weight PLGA is faster. The drug content in microspheres also has an effect on the drug release. Higher progesterone content in microspheres yields a quicker initial burst release of the drug.
In the present investigation, a poly(DL-co-glycolide) (PLGA)-based, microspheric depot system for bleomycin (BLM) has been formulated, and the same has been evaluated in-vivo in C57BL/6J mice bearing transplantable melanoma B16F1 murine solid tumour. The microparticulate delivery systems were formulated employing a water-in-oil-in-water (W/O/W) emulsion-solvent evaporation technique and characterized in-vitro. The microspheres were injected subcutaneously to form a drug depot at the site of injection in mice bearing experimental tumours and the drug was continuously infused into the systemic circulation with progressive biodegradation. The drug-loaded microspheres exhibited improved pharmacodynamic efficacy, as evidenced by retarded tumour growth kinetics. Preliminary pharmacokinetic studies illustrated controlled release of the drug into the systemic circulation over the study period to exert an anti-neoplastic action. These studies demonstrated the feasibility of employing a PLGA-based microparticulate system as an effective biodegradable, injectable, depot-forming therapeutic system for long-term administration of anti-neoplastic agents.
Poly(ortho esters) prepared by the condensation of 1,2,6-hexanetriol and an alkyl orthoacetate are viscous, semisolid materials at room temperature that can be injected using a blunt needle. When tetracycline was incorporated into these materials, complete release occurred within about 24 hours, but when small amounts of Mg(OH)2 were incorporated into the polymer release could be extended to many weeks, and a loading of 0.5 wt% resulted in sustained release of about 10 days. When adhesion was tested using bovine teeth, cohesive failure of the pure polymer occurred at a force of about 392 mN cm-2 and cohesive failure of a polymer incorporating 10 wt% tetracycline and 1 wt% (Mg(OH)2 occurred at about 118 mN cm-2. The combination of injectability, dentoadhesiveness and ability to control accurately the release of incorporated antibiotics makes these materials promising candidates for bioerodible delivery systems useful in the treatment of periodontitis. Toxicological studies are currently in progress.
Nanoparticles represent useful drug delivery systems for the specific transport of drugs to tumour cells. In the present study biodegradable nanoparticles based on gelatin and human serum albumin (HSA) were developed. The surface of the nanoparticles was modified by covalent attachment of the biotin-binding protein NeutrAvidin enabling the binding of biotinylated drug targeting ligands by avidin-biotin-complex formation. Using the HER2 receptor specific antibody trastuzumab (Herceptin) conjugated to the surface of these nanoparticles, a specific targeting to HER2-overexpressing cells could be shown. Attachment of the antibody-conjugated nanoparticles to the surface of HER2-overexpressing cells was time and dose dependent. Confocal laser scanning microscopy demonstrated an effective internalisation of the nanoparticles by HER2-overexpressing cells via receptor-mediated endocytosis. The results indicate that nanoparticles conjugated with an antibody against a specific tumour antigen holds promise, as selective drug delivery systems for the treatment of tumours expressing a specific tumour antigen. To our knowledge, this is the first study that demonstrates the effective and specific targeting of protein-based nanoparticles as drug delivery systems.
Since it is a disease mainly caused by plaque--an aggregate of various bacteria--periodontal disease can be considered a local infection. Thus, it has seemed reasonable to utilize antibiotics to suppress the intrapocket bacteria, specifically or nonspecifically. When antibiotics are administered orally, however, massive doses over a prolonged period of time are needed to attain a therapeutic effect. This increases the risk of adverse reactions as well as developing resistant strains of bacteria. To overcome these problems, local drug delivery systems (LDDS) were devised to combat the local infection. However, the intrapocket antibiotic delivery systems have yet to be fully evaluated for clinical effectiveness; to prove the therapeutic effectiveness of locally administered antibiotics, the drug must reach the base of the periodontal pocket and the effective concentration of the antibiotic against the pathogenic bacteria must be maintained for a long time. This concise review presents with figures, tables, and a comprehensive list of references the many studies which have used the various tetracyclines as LDDS to treat periodontal disease.
The availability of osteogenic proteins for orthopedic applications has led to great interest in developing delivery systems for these substances. Standard release rate models are applicable in most biological settings, but orthopedic implants usually bear mechanical loads. To determine whether a release rate model for load bearing applications must consider mechanical stress, the effects of dynamic mechanical stress on the in vitro release kinetics of two model proteins, bovine albumin (BA) and trypsin inhibitor (TI), from a biodegradable film were evaluated. Biodegradable poly(lacticco-glycolic acid) cylindrical implants with embedded proteins were subjected to cyclic three point bending loading of 720 cycles/day at 0.4 Hz for 2 weeks. Protein release into solution, swelling and mass loss changes, molecular weight degradation, and the presence of microstructural stress cracks and pores in the polymer carrier were evaluated. Cumulative BA and TI releases with time were significantly higher when a cyclic bending load was applied and increased with the magnitude of the load. Mass loss was not significantly greater, nor was swelling or molecular weight change of the polymer carrier in this 2-week interval. Pores on the surface of the polymer in the highest stress region were elongated into cracks, compared with pores in the low-stress region of the same implant, which were roughly circular. This implies that the pores probably act as stress risers to initiate cracks, which then expose more surface area, increasing protein release.
PURPOSE: The purpose of this study was to demonstrate that surgically implanted, controlled-release, biodegradable polilactofate microspheres (Paclimer) can be used safely to bypass the blood-brain barrier and deliver paclitaxel to malignant brain tumors. EXPERIMENTAL DESIGN: The rate of paclitaxel release from Paclimer microspheres submerged in PBS was measured in vitro by high-performance liquid chromatography. In vivo studies of Paclimer were performed as intracranial implants in Fischer 344 rats in the presence or absence of 9L gliosarcoma. Mantel-Cox statistics were used to assess the efficacy of Paclimer at extending survival of tumor-bearing animals compared with control implants. Paclimer implants tagged with [(3)H]paclitaxel were used to measure biodistribution of paclitaxel from the Paclimer implant. RESULTS: Paclimer released paclitaxel at a constant rate for up to 3 months in vitro. In vivo, Paclimer implants placed intracranially in rats released active drug for up to 30 days after implantation and doubled the median survival of rats bearing established 9L gliosarcomas (median survival of paclitaxel-treated animals = 35 days; median survival of control-treated animal = 16 days; P < 0.0001). Active drug was distributed throughout the rat brain based on liquid scintillation counting and TLC. Rats implanted with Paclimer demonstrated no overt signs of neurotoxicity and exhibited local cytopathological changes consistent with exposure to an antimicrotubule agent. CONCLUSIONS: Paclimer extends survival in a rodent model of glioma with minimal morbidity and optimal pharmacokinetics.
A new tadpole-shaped polymer was synthesized via the coupling reaction of poly(DL-lactide) (PLA) onto mono(6-(2-aminoethyl)amino-6-deoxy)-beta-cyclodextrin (CDen) using N,N'-Dicyclohexycarbodiimide as the catalyst. The structures of CDenPLA as the products were characterized with infrared spectrometry, nuclear magnetic resonance and their molecular weights were determined by gel permeation chromatography. The tadpole-shaped polymer possessed both a hydrophilic head that could bind some residues on a protein and a hydrophobic polylactide tail so that it could be amphiphilic. Two methods, double emulsion (DE) and nanoprecipitation (NP), were employed to fabricate the polymeric nanoparticles into which the bovine serum albumin was loaded as a model protein. The nanoparticles with a hydrophobic core of the PLA segments covered with the hydrophilic corona layer of the cyclodextrin moiety could be formed from the copolymers using NP method as identified by 1HNMR. Influence of the preparation conditions on the nanoparticles size, encapsulation efficiency and release profile in vitro was investigated. The encapsulation efficiency of the BSA-loaded nanoparticles with the average diameter of 377 nm was 71.6% under an optimized condition. The structure maintenance in the nanoparticle preparation and release in vitro was also measured via sodium dodecyl sulfate polyacrylamide gel electrophoresis and circular dichroism spectrometry. The results showed that the new copolymer could load BSA effectively and BSA kept stable after it was released from the nanoparticles.
In the past, drugs were frequently administered orally, as liquids or in powder forms. To avoid problems incurred through the utilization of the oral route of drug administration, new dosage forms containing the drug(s) were introduced. As time progressed, there was a need for delivery systems that could maintain a steady release of drug to the specific site of action. Therefore, drug delivery systems were developed to optimize the therapeutic properties of drug products and render them more safe, effective, and reliable. Implantable drug delivery systems (IDDS) are an example of such systems available for therapeutic use. The application of currently available implantable drug delivery systems is the main focus of this review. IDDS can be classified into three major categories: biodegradable or nonbiodegradable implants, implantable pump systems, and the newest atypical class of implants. Biodegradable and nonbiodegradable implants are available as monolithic systems or reservoir systems. The release kinetics of drugs from such systems depend on both the solubility and diffusion coefficient of the drug in the polymer, the drug load, as well as the in vivo degradation rate of the polymer, especially, in the case of the biodegradable systems. Controlled release of drug from the implantable pump is generally achieved utilizing the microtechnology of electronic systems and remote-controlled flow rate manipulation through the maintenance of a constant pressure difference. The third atypical class includes those which have been recently developed such as ceramic hydroxyapatite antibiotic systems used in the treatment of bone infections, intraocular implants for the treatment of glaucoma, and transurethral implants utilized in the treatment of impotence. The major advantages of these systems include targeted local delivery of drugs at a constant rate, less drug required to treat the disease state, minimization of possible side effects, and enhanced efficacy of treatment. Also, these forms of delivery systems are capable of protecting drugs which are unstable in vivo and that would normally require a frequent dosing intervals. Due to the development of such sustained release formulations, it is now possible to administer unstable drugs once a week to once a year that in the past required frequent daily dosing. Preliminary studies using these systems have shown superior effectiveness over conventional methods of treatment. However, one limitation of these newly developed drug delivery systems is the fact that their cost-to-benefit ratio (cost/benefit) is too high which restricts their use over conventional dosage forms. Hopefully, in the future, new implantable systems can be developed at a lower cost, thereby minimizing the cost-to-benefit ratio and therefore, be used extensively in standard therapeutic practice. Some of the most recently discovered implants are in the early developmental stages and more rigorous clinical testing is required prior to their use in standard practice.
The main objective of drug delivery systems is to deliver a drug effectively, specifically to the site of action and to achieve greater efficacy and minimise the toxic effects compared to conventional drugs. Amongst various carrier systems, liposomes have generated a great interest because of their versatility. Liposomes are vesicular concentric bilayered structures, which are biocompatible, biodegradable and nonimmumnogenic. They can control the delivery of drugs by targeting the drug to the site of action or by site avoidance drug delivery or by prolonged circulation of drugs. Amphotericin B (Amp B) remains the drug of choice in most systemic mycoses and also as a second line treatment for Kala azar. However, its toxic effects often limit its use. Although the liposome delivery system has been tried for several drugs, only a few have been used in patients due to the slow development of necessary large-scale pharmaceutical procedures. This paper reviews the development of the technique for liposomal Amphotericin B (L-Amp-LRC-1, Fungisome) drug delivery system in our laboratory in collaboration with the department of Biochemistry, Delhi University in India and proving the safety and efficacy of this preparation in clinical practice. It also attempts to compare the efficacy and benefits of our product for Indian patients with those of similar products and it includes facts from the publications that flowed from our work. As compared to conventional Amp B, Fungisome is infused over a much shorter period requiring a smaller volume and no premedication. It was found to be safe in patients who had developed serious unacceptable toxicity with conventional Amp B. In renal transplant patients, Fungisome did not produce any nephrotoxicity. Fungisome is effective in fungal infections resistant to fluconazole, conventional Amp B and in virgin and resistant cases of visceral leishmaniasis. The cost of any drug is of great significance, especially in India. We have therefore devoted a section of our review to the relative costs of our product and those of other commercially available products. This patient-worthy formulation is safe, efficacious and cheaper than the commercially available formulation of liposomal amphotericin B. The product has been patented and technology transferred to a pharmaceutical company for marketing. Results of postmarketing study also document safety and efficacy as observed in premarketing studies. A brief review of this work is provided here.
OBJECTIVES: This study sought to evaluate the delivery efficiency, intramural retention and antirestenotic efficacy of soluble colchicine or colchicine analogue delivered into the arterial wall after angioplasty as well as the efficacy of these medications after prolonged local release from biodegradable microparticles. BACKGROUND: Local delivery of pharmacologic agents is a potential treatment for restenosis. However, the delivery efficiency of the technique and the choice of agent to modulate cellular proliferation are unknown. It was hypothesized that restenosis would be unaffected by colchicine or a hydrophobic colchicine analogue with short intramural retention, whereas it would be reduced after prolonged local release. METHODS: Rabbit atherosclerotic femoral arteries underwent angioplasty followed by local delivery. Delivery efficiency and intramural retention of 3H-colchicine were evaluated. The effect of agents in soluble formulation or released from microparticles on angiographic and morphometric restenosis was evaluated at 2 weeks and compared with that in the control groups (angioplasty only and local infusion of carrier solution). RESULTS: Delivery of efficiency was 0.01% and intramural retention < 24 h. Neither soluble colchicine formulation reduced restenosis. Microparticles releasing the colchicine analogue reduced restenosis compared with control and colchicine microparticles but not angioplasty alone (p = 0.002). Delivery outside the artery was observed, and the long-term release of both colchicine resulted in toxicity to the adjacent musculature. CONCLUSIONS: Colchicine or the colchicine analogue did not reduce restenosis, although the long-term local release of the colchicine analogue reduced neointimal proliferation resulting from local delivery. Local delivery of cytotoxic agents with insufficient vascular specificity may be limited by toxicity to adjacent tissues resulting from a larger than expected delivery area and prolonged agent retention.
This research examines the microstructure of bioerodible polyanhydrides with an eye towards precise design of drug delivery devices. Our main hypothesis is that the bioerodible copolymer poly(1,6-bis-p-carboxyphenoxyhexane-co-sebacic anhydride) (CPH : SA) undergoes micro-phase separation at certain copolymer compositions due to differences in relative hydrophobicity of the co-monomers, resulting in thermodynamic partitioning of drugs incorporated into these copolymers. We investigate the thermal properties, degree of crystallinity, and surface microstructure of several compositions of CPH : SA using differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WAXD), and atomic force microscopy (AFM). We observe that the degree of crystallinity decreases, while the crystal lamellar thickness increases with CPH content. Phase-imaging using AFM indicates the presence of micro-domains in 20 : 80 and 80 : 20 CPH : SA, while poly(SA) and 50 : 50 CPH : SA show no micro-phase separation. Finally, drug-polymer interactions are studied by loading the polymers with different amounts of brilliant blue (hydrophilic) and p-nitroaniline (hydrophobic). DSC and WAXD analysis shows that loading hydrophobic drugs into relatively hydrophobic polymers (poly(SA)) lowers melting point that becomes more pronounced with increased drug loading.
The multiblock copolymers composed of poly(ethylene glycol)s (PEGs) and biodegradable poly(epsilon-caprolactone)s (PCLs) were synthesized through one-step condensation copolymerization with hexamethylene diisocyanate (HDI) as a coupling agent. The typical phase diagram of these multiblock copolymers in aqueous solution displayed a critical gel concentration (CGC) and an upper phase-transition temperature, which were mainly determined by the PEG/PCL block ratio, the PEG or PCL block lengths and the molecular weight. With decreasing PEG/PCL block ratio, the CGC decreased with an elevated sol-gel transition temperature on account of the enhanced hydrophobicity. The HDI/Diols ratio was used to control the molecular weight. At high molecular weights, the CGC decreased, related to the enhanced aggregation of PCL blocks and physical crosslinkage between PCL block domains due to the increased number of PCL blocks in each molecule. For the sample containing the long PCL(2000) block (M(n), 2000), the CGC dropped dramatically due to the high hydrophobicity and the poor compatibility between PCL and PEG. The dynamic phase transition process was observed by combining optical microscopy (OM) and differential scanning calorimetry (DSC) in a certain heating/cooling rate. Finally, a possible phase separation-induced gelation mechanism is suggested.
A novel biodegradable device, designed for long-lasting residual effectiveness of feeding stimulant (sugar) and insecticide (dimethoate) against apple maggot files and other insects, was formulated. The device is an 8-cm diameter fruit-mimicking sphere, consisting of 42-50% sugar entrapped in a mixture of gelatinized corn flour and wheat flour in the presence of glycerin, and coated with a layer of latex paint containing dimethoate and sugar. We found that the outer layer of paint prevents cracking of the sphere upon drying and creates a barrier to control the release of both sugar and dimethoate. Releases of each ingredient were screened first by chemical analysis and then by bioassays in the laboratory and in field cages against apple maggot flies. Chemical analysis demonstrated strong potential for controlled release of water-soluble feeding stimulant and water-insoluble insecticide measured as a function of the amount of rainfall and duration of exposure time. Field results showed greater than 70% insecticidal activity after 11 weeks of sphere exposure in an orchard. This device has the potential to be used for a variety of insect-control applications through manipulating its shape, color and texture into forms known to be attractive to target insects, and by employing various toxicants designed to be effective against such insects.
Polyhydroxyalkanonate is a typical biodegradable material, which is permitted for use in the medical and pharmaceutical fields. For its biodegradability, biocompatibility, and toxicological safety, the majority of products practically used are composed of homo-polymers of poly(lactic acid), poly(glycolic acid), and poly(epsilon-caprolactone) and their co-polymers. On the market, suture strings are still the main usage. The needs of biodegradable materials have been being gradually increased by the development of drug delivery systems, tissue engineering, and regenerative medicine. Some types of formulation, that is, mono-fibers, twisted fibers, films, fabrics, sponges, and injectable particles are developed to match each purpose. This article reviews the current clinical applications and trials of polyhydroxyalcanonate products.
Solvent evaporation technique with O/O (oil/oil) emulsion was used to prepare 5-FU (5-fluorouracil) biodegradable microspheres with a polymer of poly(dl-lactide-co-glycolide) combining lecithin as an emulsifier. In vitro drug release was conducted in phosphate buffer with pH 7.4 at 37 degrees C. For in vivo studies, 10 mg of 5-FU microspheres (containing 1 mg of 5-FU) were implanted in the conjunctival area of the rabbit eye. Rabbits were sacrificed at certain time intervals within 7 days after drug application. Samples of aqueous humor and sclera were prepared and analyzed by the high performance liquid chromatography (HPLC) method. The tested 5-FU microsphere contained 10% drug with a mean particle size of 4.4 +/- 0.6 microm. The microsphere had a burst release initially (64.9 +/- 1.5%), followed by a sustained release; the cumulative release at time points of 1, 10 and 21 days were 71.9 +/- 1.9%, 80.1 +/- 2.1% and 89.8 +/- 2.3%, respectively. For in vivo studies, aqueous humor levels showed a peak at the first sampling point (2 hr), then maintained low levels of 5-FU with a range 0.2-1 microg/mL. Scleral levels were 20-80 microg/mL during a 7-day study. Our results indicate that the prepared 5-FU microsphere provided a long-term release for more than 1 week. The preparation showed no irritation and low toxicity (< 100 microg/mL). For application to the eye, it might be potentially useful as a complement drug system in glaucoma filtration surgery.