Background: Although several classes of therapeutic agents are available to treat heart failure, the mortality is still very high in humans worldwide. Alpha-calcitonin gene related peptide (αCGRP) is a 37-amino acid neuropeptide and a potent vasodilator. Genetic and pharmacological studies established a cardioprotective role of αCGRP in normal and pathological conditions. Previously our laboratory reported that subcutaneous (s.c.) administration of αCGRP, through osmotic mini-pumps, for 28 days protected hearts against transverse aortic constriction (TAC) pressure overload-induced heart failure in mice. As αCGRP is a short-lived peptide (half-life= ~5 min in human plasma), our laboratory used an FDA-approved immunologically-inactive biopolymer, alginate, as a peptide carrier to increase the bioavailability of αCGRP in circulation. Subcutaneous administration of alginate-αCGRP microcapsules (αCGRP dose= 6 mg/kg/mouse) on alternate days, up to 28 days, improved cardiac functions and decreased cardiac cell death in the TAC-heart failure mice. 

 

Goals: Using a lower concentration of αCGRP, the goal of present study was to determine the cardioprotective pharmacological dose of alginate-αCGRP microcapsules in heart failure mice. 

 

Methods: αCGRP encapsulated alginate microcapsules (containing αCGRP dose= 2 mg/kg per mouse) of 200 µm diameter were prepared by an electrospray method. Male C57BL6 mice were divided into: i- sham, ii- sham-alginate-CGRP, iii- TAC, and iv- TAC-alginate-CGRP. Two days after TAC, sham-alginate-CGRP and TAC-alginate-CGRP groups of mice received alginate-αCGRP microcapsules (αCGRP dose= 2 mg/kg per mouse) s.c. on alternate days for 28 days. Cardiac functions (as measured by fraction shortening, FS, and ejection fraction, EF) in all groups of mice were evaluated by short-axis M-mode echocardiography. 

Results- At the end-point, i.e. 28 days of microcapsules delivery, echocardiography data showed that TAC-induced pressure overload significantly reduced EF and FS in TAC-mice compared to sham-mice. However, alginate-αCGRP microcapsules containing αCGRP dose of 2 mg/kg/mouse did not improve these cardiac function parameters in the TAC-mice.

 

Conclusions: These studies suggested that alginate-αCGRP microcapsules containing αCGRP dose 6 mg/kg/mouse is an effective concentration to protect hearts at pathophysiological levels in the pressure overload-induced heart failure mice. The success of our state-of-art alginate-based αCGRP delivery system will be significant to treat patients suffering from cardiac diseases, particularly heart failure.

 

The need for the development of novel therapeutic agents for the treatment of cardiovascular diseases-Cardiovascular diseases (CVDs) are the number one killer of men and women worldwide, including the United States. Despite the availability of several classes of therapeutic agents to treat and prevent cardiac diseases, the 5-year survival rate is still only 50%. Globally, ~17.8 million deaths were caused by CVDs in the year 2017, and it is expected to rise to >23.6 million deaths by the year 2030. Nearly 1 in 3 deaths in the United States is accounted by the CVDs and it is estimated that, by the year 2035, ~45% of the US population would have some form of CVDs. It is expected that the total direct and indirect treatment cost of CVDs in the USA will reach $1.1 trillion in the year 2035. These numbers shows that CVDs are placing a heavy financial burden on the economy and the health care system as well. Therefore, more effective therapeutic agents are needed to treat patients with cardiac diseases.

 

Development and efficacy of a peptide delivery system of a neuropeptide, alpha-calcitonin gene related peptide (α-CGRP), for the treatment of congestive heart failure-In recent years, peptide-based therapeutics are gaining attention across academic and pharmaceutical industries. Using a series of preclinical in vivo and in vitro experiments, our laboratory established that a neuropeptide α-CGRP (alpha-calcitonin gene related peptide) is a promising therapeutic agent to treat cardiac diseases. However, peptide-based drugs, as the case with α-CGRP, are difficult to use since peptides are very susceptible to the proteolytic degradation, thus present a major hurdle in advancing peptide-based therapeutics. In an attempt to overcome the peptides’ in vivo bioavailability issue, we have recently used alginate biomaterial as a drug carrier and developed an alginate based α-CGRP delivery system. Our results in a mouse model of pressure-induced heart failure demonstrated that administration of α-CGRP encapsulated alginate microcapsules protected hearts against pressure-induced heart failure in mice. The success of state-of-the-art alginate-based CGRP delivery system will overcome the stability issues associated with peptide-based therapeutics and have the potential to dramatically change conventional drug therapies used presently to treat the patient suffering from cardiovascular diseases, including heart failure, hypertension, and myocardial ischemia.