Abstract P121: A Novel Delivery of Alpha-Calcitonin Gene Related Peptide (α-CGRP) Using Alginate Microcapsules Protects Against Pressure-Overload Induced Heart Failure

Abstract

The cardioprotective role of α-calcitonin gene related peptide (α-CGRP), a 37-amino acid neuropeptide and potent vasodilator, in cardiac diseases has been established by our laboratory and others. Systemic delivery of α-CGRP decreases blood pressure in hypertensive humans, and improves hemodynamic variables in congestive heart failure (CHF) patients. However, the short half-life of the peptide (t 1/2 = ~5.5 min in serum) limits α-CGRP use in any long-term treatment regime. The present study utilized alginate-α-CGRP microcapsules for long-term continuous delivery of α-CGRP in a mouse CHF model. We used an electrospray method to prepare α-CGRP encapsulated alginate microcapsules approximately 200μm in size. The α-CGRP encapsulated microcapsules showed no cytotoxicity when incubated with the cardiac cell lines, HL-1 and H9c2 cells, for 7 days. Subcutaneous administration of microcapsules containing 150, 250, or 500μg α-CGRP lowered the systolic pressure up to 18 h, 3 days, and 7 days, respectively, in wild-type mice (measured by tail-cuff method), indicating that released α-CGRP remains biologically active. The cardioprotective effect of microcapsules released α-CGRP was examined using a transverse aortic constriction (TAC) induced pressure-overload mouse model of CHF. After two days of TAC, 500μl of alginate-α-CGRP microcapsules (containing 150μg α-CGRP) was administered in nine weeks old C57/BL6 mice on alternate days up to 28 days. Echocardiography data showed that microcapsule treatment of α-CGRP significantly preserved left ventricular fraction shortening (FS) and ejection fraction in the TAC mice (FS±SD: sham 47.2±1.5%, sham-alginate-α-CGRP 48.4±1.8%, TAC 29.5±1.4%, and TAC-alginate-α-CGRP 43.2±1.2%). α-CGRP delivery attenuated cardiac hypertrophy in TAC mice when reported as heart wt/tibia length (mg/mm±SD): sham 6.3±0.1, sham-alginate-α-CGRP 6.3±0.2, TAC 8.6±0.3, and TAC-alginate-α-CGRP 6.6±0.2. Alginate-only microcapsules did not affect these cardiac parameters. Our results show that α-CGRP delivery through alginate microcapsules protect hearts from cardiac failure. As alginate is immunologically inactive, the alginate microcapsules offer a new potential delivery paradigm for patients with heart failure.