SDF‐1 alpha Nanoglycan Complexes Exhibit Exended Retention Time and Beneficial Effect in Pulmonary Hypertension

Abstract

SDF‐1α has been known to be an important stem cell homing factor, and exhibits pro‐angiogenic activity in vivo. Exogenously delivered SDF‐1α, however, has limited retention time in tissue, which is thought to be related to protease degradation or rapid diffusion into the circulation. In the present study, we formulated SDF‐1α nanoglycan complexes by mixing SDF‐1α with dextran sulfate and chitosan. The resulting complex particles showed diameters of 600–800 nm and a zeta potential of ~−40mV. In vitro release of SDF‐1α from the nanoglycan particles was extremely slow, 1–2% after 7 days at 37°C. In cell culture studies, the nanoglycan‐incorporated SDF‐1α (SDF‐1α NP) showed the same chemotactic activity as that of free SDF‐1α. SDF‐1α NP also activated CXCR4‐mediated phosphorylation of Akt and ERK similarly as that of free of SDF‐1α. Delivery of SDF‐1α to rat lungs by intratracheal aerosolization revealed that the retention time of SDF‐1α NP in the lung was significantly longer than that of free SDF‐1α (half‐life 2.8 hr vs 36 hr). Aerosolization of SDF‐ 1α NP, but not free SDF‐1α, was found to attenuate monocrotaline‐induced pulmonary hypertension in rats. This study demonstrated that functional SDF‐1α NPs have extended retention time in the lung and is beneficial in the treatment of pulmonary hypertension in rats. Supported by NIH grant HL107192.