Neuroprotective macromolecular methylprednisolone prodrug nanomedicine prevents glucocorticoid-induced muscle atrophy and osteoporosis in a rat model of spinal cord injury.

To address the adverse side effects associated with systemic high-dose methylprednisolone (MP) therapy for acute spinal cord injury (SCI), we have developed a N-2-hydroxypropyl methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP). Intravenous Nano-MP selectively targeted to the inflamed SCI lesion and significantly improved neuroprotection and functional recovery after acute SCI. In the present study, we comprehensively assessed the potential adverse side effects associated with the treatment in the SCI rat models, including reduced body weight and food intake, impaired glucose metabolism, and reduced musculoskeletal mass and integrity. In contrast to free MP treatment, intravenous Nano-MP after acute SCI not only offered superior neuroprotection and functional recovery but also significantly mitigated or even eliminated the aforementioned adverse side effects. The superior safety features of Nano-MP observed in this study further confirmed the clinical translational potential of Nano-MP as a highly promising drug candidate for better clinical management of patients with acute SCI.

Targeted-delivery of nanomedicine-enabled methylprednisolone to injured spinal cord promotes neuroprotection and functional recovery after acute spinal cord injury in rats.

To date, no therapy has been proven to be efficacious in fully restoring neurological functions after spinal cord injury (SCI). Systemic high-dose methylprednisolone (MP) improves neurological recovery after acute SCI in both animal and human. MP therapy remains controversial due to its modest effect on functional recovery and significant adverse effects. To overcome the limitation of MP therapy, we have developed a N-(2-hydroxypropyl) methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP) that can selectively deliver MP to the SCI lesion when administered systemically in a rat model of acute SCI. Our in vivo data reveal that Nano-MP is significantly more effective than free MP in attenuating secondary injuries and neuronal apoptosis. Nano-MP is superior to free MP in improving functional recovery after acute SCI in rats. These data support Nano-MP as a promising neurotherapeutic candidate, which may provide potent neuroprotection and accelerate functional recovery with improved safety for patients with acute SCI.

Thermoresponsive Polymeric Hydromorphone Prodrug Provides Sustained Local Analgesia without Apparent Adverse Effects.

The extensive use of opioids for chronic pain management has contributed significantly to the current opioid epidemic. While many alternative nonopioid analgesics are available, opioids remain the most potent analgesics for moderate to severe pain management. In addition to the implementation of multimodal analgesia, there is a pressing need for the development of more effective and safer opioids. In this study, we developed a thermoresponsive N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based hydromorphone (HMP) prodrug (ProGel-HMP, HMP content = 16.2 wt %, in base form). The aqueous solution of ProGel-HMP was free-flowing at 4 °C but became a hydrogel when the temperature was raised to ≥37 °C, allowing sustained local retention when administered in vivo. When tested in the destabilization of the medial meniscus (DMM) mouse model of osteoarthritis (OA), ProGel-HMP was retained after intra-articular injection in the OA knee joint for at least 2 weeks postinjection, with low extra-articular distribution. ProGel-HMP was not detected in the central nervous system (CNS). A single dose of ProGel-HMP produced rapid and sustained joint pain resolution for greater than 14 days when compared to saline and dose-equivalent HMP controls, likely mediated through peripheral µ-opioid receptors in the knee joint. Systemic analgesia effect was absent in the DMM mice treated with ProGel-HMP, as evident in the lack of difference in tail flick response between the ProGel-HMP-treated mice and the controls (i.e., Healthy, Saline, and Sham). Repeated dosing of ProGel-HMP did not induce tolerance. Collectively, these data support the further development of ProGel-HMP as a potent, safe, long-acting and nonaddictive analgesic for better clinical pain management.

Single dose thermoresponsive dexamethasone prodrug completely mitigates joint pain for 15 weeks in a murine model of osteoarthritis.

In this study, we aimed to assess the analgesic efficacy of a thermoresponsive polymeric dexamethasone (Dex) prodrug (ProGel-Dex) in a mouse model of osteoarthritis (OA). At 12 weeks post model establishment, the OA mice received a single intra-articular (IA) injection of ProGel-Dex, dose-equivalent Dex, or Saline. Comparing to Saline and Dex controls, ProGel-Dex provided complete and sustained pain relief for >15 weeks according to incapacitance tests. In vivo optical imaging confirmed the continuous presence of ProGel-Dex in joints for 15 weeks post-injection. According to micro-CT analysis, ProGel-Dex treated mice had significantly lower subchondral bone thickness and medial meniscus bone volume than Dex and Saline controls. Except for a transient delay of body weight increase and slightly lower endpoint liver and spleen weights, no other adverse effect was observed after ProGel-Dex treatment. These findings support ProGel-Dex's potential as a potent and safe analgesic candidate for management of OA pain.