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Biomedical subjects

T R Tice

Publications and source records attributed to T R Tice.

At least 19 recordsLinked to original sources
PubMed1993

New advances in vaccine delivery systems.

Successful application of the next generation of vaccines will require that protection be induced with a minimal number of administrations, and that a practical approach to inducing immunity at mucosal surfaces be developed. For these reasons, vaccine-containing microspheres were formulated from the biodegradable and biocompatible copolymer poly(DL-lactide-co-glycolide) [DL-PLG]. Subcutaneous immunization of mice with 1- to 10-microns microspheres containing a toxoid vaccine of staphylococcal enterotoxin B (SEB) induced a 500-fold potentiation of the circulating antitoxin response. Strong adjuvant activity was dependent on the microspheres being no more than 10 microns in diameter and required that the antigen was within the particles. The rate of DL-PLG biodegradation is a function of the ratio of lactide to glycolide, and the co-injection of SEB toxoid microspheres formulated with two different DL-PLG ratios stimulated both a primary and an anamnestic secondary antitoxin response. When it was administered by the oral or intratracheal (IT) route, microencapsulated SEB toxoid was found to be effective in the induction of concurrent circulating and disseminated mucosal antibody responses. Female rhesus macaques immunized with a microencapsulated simian immunodeficiency virus (SIV) vaccine produced high levels of circulating anti-SIV antibodies, and following oral or IT boosting, specific antibodies were found in vaginal wash fluids. Vaginal challenge with viable homologous SIV resulted in the infection of three out of four nonimmunized but only one out of seven microsphere-immunized macaques. Thus, DL-PLG microspheres are a promising approach to the delivery of vaccines, combining adjuvant activity with controlled release and effective presentation to mucosally associated lymphoid tissues (MALT).

Adjuvants, Immunologic↗
PubMed1991

Biodegradable microspheres as a vaccine delivery system.

The utility of biodegradable and biocompatible microspheres as a vaccine delivery system for the induction of systemic and disseminated mucosal antibody responses was investigated. Intraperitoneal (ip) injection into mice of 1-10 microns microspheres, constructed of the copolymer poly(DL-lactide-coglycolide) (DL-PLG) which contained approximately 1% by weight a formalinized toxoid vaccine of staphylococcal enterotoxin B (SEB), dramatically potentiated the circulating IgG anti-toxin antibody response as compared to the free toxoid. The initiation of vaccine release was delayed in larger microspheres, and a mixture of 1-10 and 20-50 microns microspheres stimulated both a primary and an anamnestic secondary anti-toxin response following a single injection. However, neither free nor microencapsulated SEB toxoid induced a detectable mucosal IgA anti-toxin response following systemic injection. In contrast, three peroral immunizations with toxoid-microspheres stimulated circulating IgM, IgG and IgA anti-toxin antibodies and a concurrent mucosal IgA response in saliva, gut washings and lung washings. Systemic immunization with microencapsulated toxoid primed for the induction of disseminated mucosal IgA responses by subsequent oral or intratracheal (it) boosting in microspheres, while soluble toxoid was ineffective at boosting. These results indicate that biodegradable and biocompatible microspheres represent an adjuvant system with potentially widespread application in the induction of both circulating and mucosal immunity.

Administration, Oral↗
PubMed1991

Biodegradable and biocompatible poly(DL-lactide-co-glycolide) microspheres as an adjuvant for staphylococcal enterotoxin B toxoid which enhances the level of toxin-neutralizing antibodies.

Microspheres composed of biocompatible, biodegradable poly(DL-lactide-co-glycolide) (DL-PLG) and staphylococcal enterotoxin B (SEB) toxoid were evaluated as a vaccine delivery system when subcutaneously injected into mice. As measured by circulating immunoglobulin G (IgG) antitoxin titers, the delivery of SEB toxoid via DL-PLG microspheres, 1 to 10 microns in diameter, induced an immune response which was approximately 500 times that seen with nonencapsulated toxoid. The kinetics, magnitude, and duration of the antitoxin response induced with microencapsulated toxoid were similar to those obtained when an equal toxoid dose was administered as an emulsion with complete Freund adjuvant. However, the microspheres did not induce the inflammation and granulomata formation seen with complete Freund adjuvant. The adjuvant activity of the microspheres was not dependent on the superantigenicity of SEB toxin and was equally effective at potentiating circulating IgG antitrinitrophenyl levels in response to microencapsulated trinitrophenyl-keyhole limpet hemocyanin. Empty DL-PLG microspheres were not mitogenic, and SEB toxoid injected as a mixture with empty DL-PLG microspheres was no more effective as an immunogen than toxoid alone. Antigen-containing microspheres 1 to 10 microns in diameter exhibited stronger adjuvant activity than those greater than 10 microns, which correlated with the delivery of the 1- to 10-microns, but not the greater than 10-microns, microspheres into the draining lymph nodes within macrophages. The antibody response induced through immunization with microencapsulated SEB toxoid was protective against the weight loss and splenic V beta 8+ T-cell expansion induced by intravenous toxin administration. These results show that DL-PLG microsphere vaccine delivery systems, which are composed of pharmaceutically acceptable components, possess a strong adjuvant activity for their encapsulated antigens.

Adjuvants, Immunologic↗
PubMed1991

Microencapsulated dopamine (DA)-induced restitution of function in 6-OHDA-denervated rat striatum in vivo: comparison between two microsphere excipients.

Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly [DL lactide-co-glycolide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microspheres encapsulated within two different polymer excipients into denervated-striatal tissue assures a prolonged release of the transmitter in vivo. Moreover, in this regard, the results show that there were clear cut temporal differences in the effect of the two DA microsphere formulations compared in this study, probably reflecting variations in the actual composition (i.e., lactide to glycolide ratio) of the two copolymer excipients examined. This technology has considerable potential for basic research with possible clinical application.

Animals↗
PubMed1991

Effects of pituitary-testicular axis suppression in utero and during the early neonatal period with a long-acting luteinizing hormone-releasing hormone analog on genital development, somatic growth, and bone density in male cynomolgus monkeys in the first 6 months of life.

The specific role of late fetal and early neonatal gonadotropins and/or sex steroids on genital development, linear growth, and bone mass accretion remains unclear. To investigate this, we attempted to selectively suppress pituitary-testicular activation from midgestation through early infancy with a long-acting LHRH agonist (LHRHA), D-Trp6,Pro9-NEt-LHRH, in microspheres. The agonist was injected sc on days 72-81 in utero, on day 1 of life, and 3 months postnatally in male cynomolgus monkeys. Control animals were treated with placebo. We then examined the consequences of such an intervention in the first 6 months of life. In the LHRHA-treated animals, marked suppression of plasma testosterone and gonadotropin levels were evident in the first 3 months of life compared to control values. The mean testicular volumes of the LHRHA group were significantly lower at birth and in the first 2 months of life than those of the placebo group (P less than 0.05). However, by 4 months of age, the mean testicular volumes of the two groups were comparable. Similarly, the mean stretched phallic lengths of the LHRH approximately A group were significantly lower than those of the placebo group throughout the first 6 months of life (P less than 0.05). By contrast, LHRHA treatment had no effect on somatic growth, as mean body weights, total body lengths, and trunk lengths of the two groups were similar over the first 6 months of life. Mean bone widths and densities of the distal third of the left radius and the left midfemur were similar in the two groups at 1 and 6 months of life. We conclude that pituitary-testicular axis suppression with a long-acting LHRHA in utero and during early infancy results in markedly stunted penile and testicular growth without affecting general somatic growth and bone density of appendicular cortical bone in the cynomolgus monkey in the first 6 months of life. Thus, an intact fetal and neonatal pituitary-testicular axis is critical for normal genital growth. However, the sex steroid requirement for maintenance of bone mineral content of appendicular cortical bone may be lower than that necessary for normal genital development.

Aging↗
PubMed1990

Release of human serum albumin from poly(lactide-co-glycolide) microspheres.

Human serum albumin (HSA) was encapsulated in a 50:50 copolymer of DL-lactide/glycolide in the form of microspheres. These microspheres were used as a model formulation to study the feasibility of controlling the release of large proteins over a 20- to 30-day period. We show that HSA can be successfully incorporated into microspheres and released intact from these microspheres into various buffer systems at 37 degrees C. A continuous release of the protein could be achieved in physiological buffers at 37 degrees C over a 20- to 30-day period from microspheres with high protein loadings (11.6%). These results demonstrate the potential of poly(DL-lactide-co-glycolide) microspheres for continuous delivery of large proteins.

Buffers↗
PubMed1990

Controlled release of interleukin-2 from biodegradable microspheres.

We have evaluated the use of biodegradable poly(DL-lactide-co-glycolide) microspheres for the controlled release of interleukin-2 (IL-2) and its modified forms: succinyl IL-2 (SIL-2) and polyethylene glycol-modified IL-2 (PEG IL-2). We show that a microsphere formulation can be prepared from PEG IL-2 using HSA as an excipient which, after an initial burst, releases 2-3% PEG IL-2 per day in a bioactive form continuously over a 20- to 30-day period.

Blotting, Western↗
PubMed1989

Vaccine-containing biodegradable microspheres specifically enter the gut-associated lymphoid tissue following oral administration and induce a disseminated mucosal immune response.

Biodegradable and biocompatible microspheres have been investigated for their usefulness as a vaccine delivery system for both parenteral and enteral immunization. Microspheres composed of poly(DL-lactide-co-glycolide) which contained a toxoid vaccine of Staphylococcal enterotoxin B were found to strongly potentiate the circulating anti-toxin antibody response following intraperitoneal injection. Following oral administration, microspheres less than 10 microns in diameter were specifically taken up into the Peyer's patches of the gut-associated lymphoid tissue, where those greater than or equal to 5 microns remained fixed for an extended period. Microspheres less than 5 microns were disseminated within macrophages to the mesenteric lymph nodes, blood circulation and spleen. Oral immunization with enterotoxoid-containing microspheres induced circulating toxin-specific antibodies and a concurrent secretory IgA anti-toxin response in saliva, gut wash fluids and bronchial-alveolar wash (BAW) fluids. In contrast, soluble enterotoxoid was completely ineffective as an oral immunogen.

Adjuvants, Immunologic↗
PubMed1989

Immune responses to influenza virus in orally and systemically immunized mice.

In our studies on the induction of an immune response by oral immunization, we have explored the potential of a novel approach for antigen delivery by microencapsulation. This procedure preserved the immunogenicity of the influenza virus introduced by either systemic or oral routes. Furthermore, the levels of specific antibodies in serum and in saliva were enhanced and lasted longer (up to 4 months) in animals immunized with of antigens in microencapsulated form than in animals immunized with equal doses of free suspension. Preliminary challenge experiments showed a correlation between levels of antibodies and protection. All mice systemically immunized were protected against the virus, while mice orally immunized with lower doses of microencapsulated antigen had better survival rates than those immunized with higher doses. Additional experiments suggested that low doses of immunogen were able to generate better protective immunity than high doses, which may instead be tolerogenic. Further experiments with a well characterized microencapsulated antigen (size of microcapsules, time of release of antigen, as well as its dose and form) will be necessary to establish conditions for optimal immunization protocols applicable for the oral or systemic routes.

Administration, Oral↗
PubMed1989

Biodegradable microspheres: vaccine delivery system for oral immunization.

The potential of biocompatible and biodegradable microspheres as a controlled release oral vaccine delivery system has been examined. Orally-administered 1-10 micron microspheres composed of poly (DL-lactide-co-glycolide) were specifically taken up into the Peyer's patch lymphoid tissue of the gut, where those greater than or equal to 5 micron remained for up to 35 days. Microspheres less than 5 micron disseminated within macrophages to the mesenteric lymph nodes and spleen. In contrast to soluble staphylococcal enterotoxin B toxoid, oral immunization with enterotoxoid in microspheres induced circulating toxin-specific antibodies and a concurrent secretory IgA anti-toxin response in saliva and gut fluid.

Administration, Oral↗
PubMed1988

Implantable microencapsulated dopamine (DA): a new approach for slow-release DA delivery into brain tissue.

Biodegradable controlled-release systems constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional and histochemical observations, indicating that implantation of DA microcapsules into striatal tissue assures a prolonged release of the transmitter in situ. This technology has considerable potential for basic and possibly also clinical research.

Animals↗
PubMed1986

Intraoral effects of a fluoride-releasing device on acid-softened enamel.

Among the anticaries benefits of fluorides is the remineralization of incipient carious lesions. There is increasingly convincing evidence that low-potency fluoride agents applied frequently are effective in remineralizing early carious lesions. This study of in vivo remineralization used an intraoral appliance with demineralized enamel slabs mounted in the appliance and an innovative method of fluoride delivery, the fluoride-releasing device, which releases a controlled amount of fluoride (0.3 mg fluoride every 24 hours) on exposure to saliva. After control and treatment periods of 7 and 30 days, the enamel specimens were removed from the appliance and evaluated for microhardness, acid resistance, and fluoride uptake. The treated specimens significantly exceeded the values of their corresponding controls in all parameters measured, indicating that considerable remineralization of the treated enamel had occurred at both 7 and 30 days. Although the longer period of treatment produced greater results, considerable effects were observed after 7 days. This model system provided for an in vivo environment to study the effects of treatment of the FRD and allowed for subsequent recovery of the enamel specimens for evaluation. The results of this study are encouraging with respect to the efficacy of a fluoride-releasing device but indicate that subsequent clinical testing of the effects of FRDs on incipient carious lesions in the natural dentition of human subjects is necessary.

Adult↗
PubMed1985

Long-acting injectable microsphere formulation for the parenteral administration of levonorgestrel.

The pharmacokinetic and pharmacodynamic effects of a long-acting formulation of levonorgestrel microencapsulated in a biodegradable polymer poly(DL-lactide-CO-glycolide) was tested in baboons. The polymer microspheres provided continuous release of levonorgestrel for up to 6 months following a single intramuscular injection. The treatment inhibits ovarian function for 3-6 months, depending on the dose. The duration and pattern of levonorgestrel release varies according to the quality and size of the microspheres. The microsphere delivery system offers a promising new approach to developing a long-acting injectable contraceptive based on levonorgestrel.

Animals↗
PubMed1985

Studies of a controlled-release microcapsule formulation of an LH-RH agonist (D-Trp-6-LH-RH) in the rhesus monkey menstrual cycle.

It has been shown that continuous administration of LH-RH agonists inhibits ovulation in many species, including human and nonhuman primates. However, the need of daily injections or intranasal application of the LH-RH agonists makes this contraceptive approach impractical. In addition, due to the repeated daily administration of the LH-RH analogues and their bioavailability, serum levels of gonadotropins and estradiol present wide variations and are often associated with irregular bleeding and/or endometrial hyperplasia. This experiment was designed to study the effects on ovulation and the hormonal profile during the rhesus monkey menstrual cycle of a system that continuously delivers a potent agonist of LH-RH (D-Trp-6-LH-RH encapsulated in poly [DL-lactide-co-glycolide]). Subjects were divided into two groups: On day 1 of the cycle, monkeys received a single subcutaneous injection of microcapsules containing D-Trp-6-LH-RH at a release rate of 13.6 micrograms/day (Group 1) or placebo microcapsules (Group 2). Ovulation dates were significantly delayed in animals from Group 1 (50 +/- 3 days) as compared to those in group 2 (20 +/- 2 days). Luteal phases following ovulation were normal in animals of both groups, as determined by length and serum progesterone levels. No significant differences on baseline levels of FSH and LH were observed between the two groups of animals. Post-treatment cycles were ovulatory and presented normal luteal phases and hormone concentrations as compared to the non-treated animals of our colony. The present data show for the first time that a controlled-release microcapsule formulation that delivers an agonist of LH-RH can effectively suppress ovulation when injected in a single dose in non-human primates.

Animals↗
PubMed1984

Controlled release of a luteinizing hormone-releasing hormone analogue from poly(d,l-lactide-co-glycolide) microspheres.

The performance in vivo of nafarelin acetate, a potent analogue of luteinizing hormone-releasing hormone, microencapsulated in poly(d,l-lactide-co-glycolide), was evaluated. The influence of polymer composition and molecular weight on the estrus-suppressing activity of the microspheres in female rats was determined. Compound release was shown to be effected by polymer erosion rather than by diffusion. A triphasic release of compound was observed, which was adjusted by altering the critical parameters of the polymer. A mechanism for the release of the compound was proposed. The primary release phase was compound loss by diffusion from the surface of the microspheres. The secondary phase of subeffective rates of release occurred concomitantly with polymer hydrolysis and a decrease in its molecular weight, although it remained insoluble. Dissolution of low-molecular weight fragments and erosion of the bulk of the polymer then initiated the tertiary phase of release of compound.

Animals↗
PubMed1984

Long-acting delivery systems for peptides: inhibition of rat prostate tumors by controlled release of [D-Trp6]luteinizing hormone-releasing hormone from injectable microcapsules.

Intramuscular injection of [6-D-tryptophan]-luteinizing hormone-releasing hormone [( D-Trp6]LH-RH) in microcapsules of poly(DL-lactide-co-glycolide), designed to release a controlled dose of the peptide over a 30-day period, decreased the weights of androgen-dependent Dunning prostate tumors in rats and suppressed serum testosterone levels more effectively than daily subcutaneous administration of equivalent or double doses of unencapsulated [D-Trp6]LH-RH. The microcapsules or daily injections of [D-Trp6]LH-RH also significantly decreased tumor volumes. Microcapsules of [D-Trp6]LH-RH or related analogs that can be injected once a month should make the treatment of patients with prostate carcinoma and other neoplasms or disorders more convenient and efficacious.

Animals↗