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Intramuscular injection of [6-D-tryptophan]-luteinizing hormone-releasing hormone ([D-Trp6]LH-RH) inmicrocapsules 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 last from a few minutes to several hours. These modes of administration, with fluctuating blood levels of the peptide, may not achieve the optimal pharmacological effects. Consequently, higher-dosage regimens and greater frequency of administration may be needed to obtain these effects. A peptide administered by a controlled delivery system that would lead to a constant release over a prolonged period of time could provide a continuous biological effect. Recently, a polymer of poly(DL-lactide-co-glycolide) (PLG) has been used to formulate microcapsules with steroids for long-acting contraceptive delivery systems (22)(23)(24) MATERIALS AND METHODSMale (Copenhagen x Fisher) F1 rats bearing the androgendependent well-differentiated R3327H Dunning rat prostate adenocarcinoma were provided by Norman Altman (Papanicolaou Cancer Research Institute, Miami, FL). Approximately 150 days after the transplantation, the tumors were palpable and the experiment began. Tumors were measured weekly with microcalipers and tumor volumes were calculated as previously described (12, 13

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 i,m 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 jim in diameter exhibited stronger adjuvant activity than those > 10 ,um, which correlated with the delivery of the 1to 10-,um, but not the >10-jim, 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 Vi8' 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.

The potential of biocompatible and biodegradable microspheres as a controlled release oral vaccine delivery system has been examined. Orally-administered 1-10 11m microspheres composed of poly (DL-Iactide-co-glycolide) were specifically taken up into the Peyer's patch lymphoid tissue of the gut, where those ~ 5 !lID remained for up to 35 days. Microspheres < 5 11m 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.