Poster U1 - Injectable Hydrogels Incorporating Microparticles as a Controlled Release System for Local Targeted Delivery of Sunitinib to Stellate Ganglion

Introduction: Autonomic control of the heart significantly influences the development of life-threatening arrhythmias that can lead to sudden cardiac death, with sympathetic activity known to be upregulated during these conditions. Therefore, the sympathetic nerves present a compelling therapeutic target for treatment. Surgical cardiac sympathetic denervation has emerged as a promising treatment option for people refractory to less invasive medical options.1 The stellate ganglion (SG) is a part of the sympathetic nervous system that has important regulatory effects on several human tissues and organs in the upper body. However, current methods for chemical treatment of sympathetically mediated arrhythmias offer only short-term effect by temporarily blocking stellate neuronal activity with local anesthetics (i.e., SG blockade), and recurrent drug-resistance of SG will necessitate invasive surgical stellate ganglionectomy for cardiac arrhythmia patients. In this study, we have developed a hyaluronic acid (HA) based injectable hydrogels with encapsulating sunitinib (SU) loaded poly(D,L-lactide-co-glycolide) (PLGA) microspheres as a potential sustained-release system for local targeted delivery of SU to specifically disrupt the vascular endothelial growth factor (VEGF) signaling pathway in the SG.

Materials and

Methods: We first encapsulated SU within PLGA microspheres (MS) by using oil-in-water (O/W) technique(Fig. 1A).2 In briefly, PLGA will be dissolved in chloroform. Then SU will be prepared in DMSO and then added to the PLGA-chloroform (1:20 v/v). After adding 1% polyvinyl alcohol (PVA) solution, the mixture will be sonicated at 20% amplitude for 20 s twice. The emulsion will be dropwise added to 0.1% PVA solution (1:20 v/v) and then stirred at 300 rpm for 3 h. The PLGA microspheres will be collected after centrifugation at 5000 rpm for 10 min. Then each 200 mg of PLGA MS will be dispersed in 100 μl of 2% HA-SH solution and the hydrogels will be formed due to disulfide bond formation. Then, SU loaded PLGA microspheres were mixed with thiolated HA hydrogels. The SU/PLGA MS/HA-SH were locally injected into rat SGs.

Results, Conclusions, and Discussions: The obtained SU-PLGA MS had spherical morphology and had an average diameter of 1.5 μm (Figure 1B). The loading efficiency of SU was calculated by subtracting the weight of the free drug in the supernatant from the total weight of drug added to PLGA. About 5.4% (w/w) loading efficiency in PLGA could be achieved. The hydrogels were formed due to the disulfide bond formation. The SU loaded hydrogels could be injected through an insulin needle (29 G) (Figure 1C). The hydrogels with or without PLGA MS had stable rheological properties demonstrated by the frequency sweep of rheological test (Figure 1D). The incorporated SU could be sustainedly released from PLGA MS and HA hydrogels for at least 21 days (Figure 1E). The SU loaded hydrogels were successfully injected into the SG (5 μl hydrogels with 10 mg PLGA microspheres containing 0.5 mg SU/each side) after exposing SG in the normal rats (Figure 1F), and the release of SU effectively disrupted the SG vascular structure demonstrated by decreasing CD31 expressions (Figure 1G).
We successfully developed hydrogels incorporating SU-loaded PLGA microparticles delivery system for long-term drug release. The SU loaded hydrogels were successfully injected into the SG after exposing SG in the normal rats, and the release of SU effectively disrupted the SG vascular structure. In our further study, we will further validate the efficacy of SU loaded hydrogels in ablating the SG in myocardial infarction rat.

Acknowledgements (Optional): R21HL170127; UNMC Center for Heart and Vascular Research, Vascular Research Program Travel Award