(L-464) Controlled Delivery of Muscarinic Receptor Agonists to Aid Xerostomia After Head/Neck Radiotherapy

Introduction::

Xerostomia due to head/neck cancer radiotherapy can cause dysphagia, oral candidiasis, tooth decay, and issues with swallowing and speech.[1] No permanent solutions have been proposed [2] but an M3 muscarinic agonist pilocarpine has shown promising results in salvia secretion.[3] In this study we propose an injectable granular hydrogel system. This hydrogel would be pH responsive and would target the understudied primary salivary myoepithelial cells with a pH dependent pilocarpine to aid in the release of saliva. This solution can aid in saliva secretion while preventing dilution of the pilocarpine in the oral cavity and unwanted exposure to other secretory glands.

Materials and Methods::

The Hydrogel Microparticles (HMPs) will be synthesized via inverse emulsion polymerization. Hyaluronic acid (HA) will react to the divinyl sulphone in an inverse emulsion droplets of aqueous sodium hydroxide in 2,2,4- trimethylpentane with it being stabilized by dioctyl sulfosuccinate sodium salt and 1-heptanol. [4] The HMPs will be embedded into an HA based commercial hydrogel system (Glycosil, Advanced Biomatrix). The myoepithelial cells will be freshly isolated from mouse tissue following our earlier reports.[5] To evaluate the in vitro drug release, the myoepithelial cells in the hydrogel will be tested for its pilocarpine release quantities via HPLC (high-performance liquid chromatography) [6] will be performed in a shimadzu prominence-i , LC-2030C Plus in a c18 Column at post-encapsulation days of 3, 7, 14, and 28. The experiments will be done in triplicates.

Results, Conclusions, and Discussions::

The development of HMPs were optimized to achieve particles with homogenous size distribution and morphology. Scanning electron microscopy (SEM) imaging of the particles show the particles as dispersed and homogenous in size (Figure 1). Further size analysis using dynamic light scattering (DLS) and Focused ion beam (FIB) SEM will be performed before starting the pilocarpine release study. Ongoing experiments are focusing on tissue retrieval and primary myoepithelial cell isolation.
Our injectable doubly cross-linked pH responsive hyaluronic acid-based hydrogel system exhibits reliable pilocarpine release within an acidic system, resistance to hyaluronic degradation, and stiff structure that can retain its shape for more than 28 days.[7] This hydrogel can aid with patients suffering from radiotherapy-induced xerostomia by providing local and targeted delivery of on-demand saliva secretion.

Acknowledgements (Optional): : This study is funded by South Dakota State university Disease, Drug, and Delivery Center, Pilot Grant Program.

References (Optional): :

1. Onjukka, E., et al., Modeling of xerostomia after radiotherapy for head and neck cancer: A registry study. Frontiers in oncology, 2020: p. 1647.


2. Ozdemir, T., et al., Biomaterials-based strategies for salivary gland tissue regeneration. Biomater Sci, 2016. 4(4): p. 592-604.


3. Jensen, S.B., et al., Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients. J Natl Cancer Inst Monogr, 2019. 2019(53).


4. Jha, A.K., et al., Structural Analysis and Mechanical Characterization of Hyaluronic Acid-Based Doubly Cross-Linked Networks. Macromolecules, 2009. 42(2): p. 537-546.


5. Ozdemir, T., et al., Bottom-up assembly of salivary gland microtissues for assessing myoepithelial cell function. Biomaterials, 2017. 142: p. 124-135.


6. Chou, S.F., L.J. Luo, and J.Y. Lai, In vivo Pharmacological Evaluations of Pilocarpine-Loaded Antioxidant-Functionalized Biodegradable Thermogels in Glaucomatous Rabbits. Sci Rep, 2017. 7: p.42344.


7. Ozdemir, T., et al., Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D. ACS Biomater Sci Eng, 2016. 2(12): p. 2217-2230.