(534f) Controlling Polymer Self-Assembly and Ordering in the Presence of Oil and Small Molecules for Non-Invasive Therapeutic Delivery

Poloxamer 407 (P407) is a nontoxic ABA triblock polymer widely used in non-invasive therapeutic delivery for its thermoresponsive solution-to-gel behavior in water. With an increase in temperature, P407 chains self-assemble into micelles and eventually a stiff micellar cubic phase. P407 formulations used for delivery across the ear drum and other biological barriers are cleverly designed to undergo this thermoresponsive transition at body temperature, allowing for facile application as a liquid but formation of a soft solid upon contacting the body. However, in P407-only hydrogels, the gel transition temperature, modulus, and structure are all dictated by polymer concentration, preventing independent tuning of these properties for clinical translation. Further, for therapeutics to traverse biological barriers and treat disease, effective chemical permeation enhancers (CPEs) must be incorporated into the formulation. However, the inclusion of CPEs limits formulation stability, solubility, and modulation of thermal and rheological properties.

To overcome these issues and precisely control the properties of P407 hydrogels for non-invasive therapeutic delivery, we have employed two new strategies; the resulting formulations are characterized using a combination of rheology, differential scanning calorimetry (DSC), and small-angle X-ray scattering (SAXS). In the first, we incorporate reverse poloxamers (RPs), containing the same blocks as poloxamers but organized in a BAB fashion, to effectively decouple gelation temperature from polymer concentration and gel modulus. In the second approach, we employ a new class of oil-based CPEs to facilitate therapeutic delivery. Unlike is typically observed upon adding small molecule CPEs, here a hybrid poloxamer emulsion/gel is formed due to the low CPE solubility. Resulting formulations that combine these two strategies exhibit novel rheological and structural transitions in response to increasing temperature; we also identify ordering at substantially lower polymer concentrations and dynamic moduli than is typically observed in such formulations. Beyond providing fundamental insight into how oil and small polymer additives can be used to control self-assembly and ordering in these hybrid systems, the new formulations retain good gelation properties while enhancing therapeutic delivery. This knowledge can be subsequently utilized to design better thermoresponsive P407 hydrogels with precisely-tunable gelation temperatures, morphologies, and mechanical properties.