A Novel Drug Delivery of Cardioprotective ⍺-CGRP Using Alginate Microcapsules in Pressure-Overload Induced Heart Failure
Andrew Hess, Ambrish Kumar, Marwa Belhaj, Donald J. DiPette, Jay Potts
Alpha-calcitonin gene-related peptide (α-CGRP), a 37 amino acid neuropeptide and potent vasodilator, also has known inotropic as well as chronotropic effects in the cardiovascular system. Our laboratory as well as other research groups previously established the cardioprotective role of α-CGRP in various cardiovascular diseases. Due to the short half-life of α-CGRP in vivo, it cannot be used as a therapeutic agent for long term treatment regimen in humans. This project’s purpose was to develop a novel drug delivery system allowing for prolonged release of α-CGRP in vivo, as well as obtaining the targeted drug response. We utilized an FDA approved alginate polymer, a natural polysaccharide isolated from seaweed, and prepared α-CGRP filled alginate microcapsule of 200 m by electrospray method. Our laboratory used four groups of mice (sham, sham-α-CGRP, TAC, and TAC-α-CGRP) and performed transaortic constriction (TAC) procedure to develop pressure-overload induced heart failure in TAC groups. Two days post TAC, alginate-α-CGRP microcapsules (150μg) were administered subcutaneously on alternating days until day 28. To measure heart function, short axis 2D echocardiograph was performed before TAC, and on every seventh day after microcapsule delivery. After 28 days, all groups of mice were sacrificed, and heart tissue was collected for histology and biochemical analysis. Our echocardiography and histochemical data demonstrated that TAC procedure reduced heart function (% fraction shortening (FS) and ejection fraction (EF)), increased cardiac hypertrophy and levels of apoptosis and oxidative stress in left ventricles. α-CGRP microcapsule preserved heart function and reduced apoptotic cell death and oxidative stress in TAC left ventricles compared to sham. These results show that α-CGRP alginate capsules are beneficial in protecting the heart from cardiac failure. The immunologic inactivity of alginate allows its use as a microcapsule in humans, breaching a new paradigm in drug delivery for the treatment of heart failure patients.