CXCL1 microspheres: a novel tool to stimulate arteriogenesis

<div><p></p><p><i>Context</i>: After arterial occlusion, diametrical growth of pre-existing natural bypasses around the obstruction, i.e. arteriogenesis, is the body’s main coping mechanism. We have shown before that continuous infusion of chemokine (C-X-C motif) ligand 1 (CXCL1) promotes arteriogenesis in a rodent hind limb ischemia model.</p><p><i>Objective</i>: For clinical translation of these positive results, we developed a new administration strategy of local and sustained delivery. Here, we investigate the therapeutic potential of CXCL1 in a drug delivery system based on microspheres.</p><p><i>Materials and methods</i>: We generated poly(ester amide) (PEA) microspheres loaded with CXCL1 and evaluated them <i>in vitro</i> for cellular toxicity and chemokine release characteristics. <i>In vivo</i>, murine femoral arteries were ligated and CXCL1 was administered either intra-arterially via osmopump or intramuscularly encapsulated in biodegradable microspheres. Perfusion recovery was measured with Laser-Doppler.</p><p><i>Results</i>: The developed microspheres were not cytotoxic and displayed a sustained chemokine release up to 28 d <i>in vitro</i>. The amount of released CXCL1 was 100-fold higher than levels in native ligated hind limb. Also, the CXCL1-loaded microspheres significantly enhanced perfusion recovery at day 7 after ligation compared with both saline and non-loaded conditions (55.4 ± 5.0% CXCL1-loaded microspheres versus 43.1 ± 4.5% non-loaded microspheres; <i>n</i> = 8–9; <i>p</i> < 0.05). On day 21 after ligation, the CXCL1-loaded microspheres performed even better than continuous CXCL1 administration (102.1 ± 4.4% CXCL1-loaded microspheres versus 85.7 ± 4.8% CXCL1 osmopump; <i>n</i> = 9; <i>p</i> < 0.05).</p><p><i>Conclusion</i>: Our results demonstrate a proof of concept that sustained, local delivery of CXCL1 encapsulated in PEA microspheres provides a new tool to stimulate arteriogenesis <i>in vivo</i>.</p></div>