The Development of a Macromolecular Analgesic for Arthritic Pain

Abstract

The addictive potential of clinically-used opioids due to their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target to the arthritic joint after systemic administration in a rodent model of monoarticular adjuvantinduced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test, and were observed to be similar to doseequivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, co-localized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain.

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

“…With the introduction of a neighboring benzene ring next to the hydrazone bond, an electron conjugation was produced, which stabilized the linker and slowed down its cleavage 44 and HMP release, contributing to a more sustained local analgesic effect than the previously reported P-HMP. 38 The newly synthesized ProGel-HMP has a weight-average molecular weight (M w ) of 12.5 kDa with a narrow dispersity (Đ = 1.03). Its aqueous solution (20 w/v%) is thermoresponsive (Figure 1A), transitioning from a free-flowing fluid at 4 °C to a hydrogel at 37 °C.…”

“…This physical mechanism for the local retention and gradual release of ProGel-HMP and the use of a more stable hydrazone linker for HMP conjugation are most likely responsible for its drastically improved duration of analgesia when compared to P-HMP. 38 The chronic nature of joint pain associated with the DMM model enables testing of the analgesic effect of ProGel-HMP and its potential for tolerance development. While it is a plausible option for temporary pain relief of acute arthritis pain flare in human subjects with OA joint pain, the 14-day local analgesia duration offered by ProGel-HMP in this study is unlikely to be applicable for general management of chronic OA pain, even with the potential adjustment of the duration by introducing a hydrophobic counterion.…”

“…It is in this context we previously developed an N -(2-hydroxypropyl)-methacrylamide (HPMA) copolymer-based hydromorphone (HMP) prodrug (P-HMP) that can be administered systemically and then localized to sites of pathology associated with inflammation and autoimmune diseases . We observed the passive targeting of P-HMP to inflamed arthritic joints and sustained pain relief with minimal systemic analgesia for 1–2 days in the monoarticular adjuvant-induced arthritis (MAA) rat model of inflammatory arthritis through a mechanism we have termed as Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS). , Specifically, P-HMP extravasates through “leaky vessels” at sites of local inflammatory pathology.…”

Triptolide and l-ascorbate palmitate co-loaded micelles for combination therapy of rheumatoid arthritis and side effect attenuation

“…Some studies have shown that vitamin C plays a significant protective role by maintaining the antioxidant activity of hydroxyl oxidase and reducing reactive oxygen species and tissue oxidative damage. In addition, it can inhibit the triptolide-induced apoptosis in renal tubular epithelial cells by inhibiting the occurrence of oxidative stress (Dennis & Witting, 2017 ; Xu et al., 2019 ). Here, triptolide loaded nanoparticles were prepared by using vitamin C derivatives as the carrier, which could reduce some side effects of TP and guarantee the therapeutic effect for RA.…”

Novel Carboxylated Chitosan-Based Triptolide Conjugate for the Treatment of Rheumatoid Arthritis

“…Moreover, the cartilage and bone damage is caused by osteoclasts, activated synovial fibroblasts and chondrocytes in inflammatory arthritis [3]. Currently available anti-rheumatic drugs, including non-steroidal drugs, glucocorticoids, and biological agents, cannot cure RA radically but only relieve its symptoms and progression [4,5]. In China, herbal medicines have been extensively utilized as alternative RA drugs for decades [6,7].…”