Abstract P106: Development Of An Oral Drug Delivery System For The Cardio-protective Neuropeptide Alpha-calcitonin Gene Related Peptide

Alpha-calcitonin gene related peptide (α-CGRP) is a promising neuropeptide for the treatment of cardiovascular disease. We have developed an alginate biomaterial-based delivery system which increases the peptide’s bioavailability and have shown that subcutaneous delivery of alginate-CGRP microcapsules significantly improved cardiac function in pressure overload-induced heart failure in mice. The goal of this study is to develop efficient alginate microcapsule formulations for oral delivery of α-CGRP. An electrospray method was used to prepare four different formulations of alginate-CGRP microcapsules all of 200 μm diameter- i)- alginate-CGRP microcapsules, ii)- alginate-CGRP microcapsules with UV-light exposure, iii)- poly-L-ornithine (PLO) coated alginate-CGRP microcapsules, and iv)- PLO alginate-CGRP microcapsules with UV-light exposure. The stability of the microcapsules in the digestive tract was evaluated in deionized water, simulated gastric fluid (SGF; pH 1.2), and simulated intestinal fluid (SIF; pH 6.8). Over time, the size of all four microcapsule formulations remained almost unchanged in SGF, however all four of the microcapsule formulations swelled in presence of SIF. Compared to deionized water, the size of alginate-CGRP microcapsules after 6 h incubation in SIF increased by 1.7 fold. Since all four formulations yielded similar results, we chose to further study the alginate-CGRP microcapsules in vivo . To determine the bioactive nature of the released peptide, alginate microcapsules containing α-CGRP in doses of 1, 3, and 10 (mg/kg b.wt) were fed to male C57BL/6 mice via oral gavage. Systolic blood pressure (SBP) was subsequently measured by a tail-cuff method. α-CGRP microcapsules reduced SBP in a time-dependent manner. Alginate-CGRP at 1 and 3 mg/kg lowered the SBP by 25 mmHg for up to 4 h and 48 h, respectively. However, 10 mg/kg alginate-CGRP initially reduced SBP to undetectable levels which ultimately returned to baseline level by day 7. These studies indicate that alginate microcapsules can withstand the low pH of the stomach and the release of the peptide is bioactive in vivo . Thus, alginate microcapsules may provide an ideal formulation to deliver α-CGRP orally for the long-term treatment of cardiac diseases.