In order to establish a homing signal in the lung to recruit circulating stem cells for tissue repair, we formulated a nanoparticle, SDF-1α NP, by complexing SDF-1α with dextran sulfate and chitosan. The data show that SDF-1α was barely released from the nanoparticles over an extended period of time in vitro (3% in 7 days at 37°C); however, incorporated SDF-1α exhibited full chemotactic activity and receptor activation compared to its free form. The nanoparticles were not endocytosed after incubation with Jurkat cells. When aerosolized into the lungs of rats, SDF-1α NP displayed a greater retention time compared to free SDF-1α (64% vs. 2% remaining at 16 hr). In a rat model of monocrotaline-induced lung injury, SDF-1α NP, but not free form SDF-1α, was found to reduce pulmonary hypertension. These data suggest that the nanoparticle formulation protected SDF-1α from rapid clearance in the lung and sustained its biological function in vivo.

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.