Thermogelling PLGA-PEG-PLGA used in development of 4-aminopyridine delivery system for treatment of paralysis

 

Paralysis can occur in cases of traumatic injuries from a variety of causes (car-crash, military action, industrial accidents, etc.) which lead to either severing or substantial injury to nerve tissue. Because nerve tissue does not normally heal itself, often this paralysis can be permanent leaving a patient unable to move from the point of the injury down (i.e. confined to a wheelchair). Recently, researchers at Pennsylvania State University used PLGA-PEG-PLGA (AK097) to create a delivery system for 4-aminopyridine, a drug which acts to enhance nerve repair. This research holds promise to improve treatment options for debilitating injuries. Read more: Manto, Kristen M., Prem Kumar Govindappa, Daniele Parisi, Zara Karuman, Brandon Martinazzi, John P. Hegarty, MA Hassan Talukder, and John C. Elfar. "(4-Aminopyridine)–PLGA–PEG as a Novel Thermosensitive and Locally Injectable Treatment for Acute Peripheral Nerve Injury." ACS Applied Bio Materials (2021). https://pubs.acs.org/doi/abs/10.1021/acsabm.0c01566

“Traumatic peripheral nerve injury (TPNI) represents a major medical problem that results in loss of motor and sensory function, and in severe cases, limb paralysis and amputation. To date, there are no effective treatments beyond surgery in selective cases. In repurposing studies, we found that daily systemic administration of the FDA-approved drug 4-aminopyridine (4-AP) enhanced functional recovery after acute peripheral nerve injury. This study was aimed at constructing a novel local delivery system of 4-AP using thermogelling polymers. We optimized a thermosensitive (4-AP)–poly(lactide-co-glycolide)–b-poly(ethylene glycol)–b-poly(lactide-co-glycolide) (PLGA–PEG–PLGA) block copolymer formulation. (4-AP)–PLGA–PEG exhibited controlled release of 4-AP both in vitro and in vivo for approximately 3 weeks, with clinically relevant safe serum levels in animals. Rheological investigation showed that (4-AP)–PLGA–PEG underwent a solution to gel transition at 32 °C, a physiologically relevant temperature, allowing us to administer it to an injured limb while subsequently forming an in situ gel. A single local administration of (4-AP)–PLGA–PEG remarkably enhanced motor and sensory functional recovery on post-sciatic nerve crush injury days 1, 3, 7, 14, and 21. Moreover, immunohistochemical studies of injured nerves treated with (4-AP)-PLGA-PEG demonstrated an increased expression of neurofilament heavy chain (NF-H) and myelin protein zero (MPZ) proteins, two major markers of nerve regeneration. These findings demonstrate that (4-AP)–PLGA–PEG may be a promising long-acting local therapeutic agent in TPNI, for which no pharmacologic treatment exists.”