Table 2 Summary of studies using block copolymers as a treatment in DMD models in vivo
Copolymer | Pathophysiology | DMD model | Treatment time | Dosage | Delivery route | Results | References |
|---|---|---|---|---|---|---|---|
P188 | Cardiomyopathy | mdx | Pre-treatment (30Â min) | 460Â mg/kg | i.v. | P188 significantly improved cardiac hemodynamic response and animal survival during cardiac stress testing | Yasuda et al. (2005) [80] |
P188 | Skeletal muscle | mdx | Pre-treatment (30 min) | 600–1800 mg/kg | i.p. | No significant difference in % EBD penetration in rectus femoris muscle fibers in P188 treated mdx mice exercised by downhill treadmill running | Quinlan et al. (2006) [150] |
P188 | Cardiomyopathy | GRMD | 8Â weeks | 60Â mg/kg/hr | i.v. | Chronic P188 treatment normalized serum cTnI levels, blocked increases in heart failure marker BNP, significantly decreased cardiac fibrosis, and prevented dilated cardiomyopathy. Cardiac hemodynamic function in response to dobutamine stress was significantly improved compared to saline treatment. Serum CK levels were not affected. | Townsend et al. (2010) [148] |
P188 | Cardiomyopathy | mdx | 2–4 weeks | 460 mg/kg | i.p. | P188 treatment prevented a decrease in cardiac function in response to isoproterenol stress testing. Treated mice did not show significant differences in cardiac fibrosis but had increase in EBD positive fibers, these hearts showed increased systolic function compared to untreated hearts. | Spurney et al. (2010) [149] |
P188 | Skeletal muscle | mdx | Pre-treatment 2-week daily | 30Â mg/kg, 460Â mg/kg | i.p. | Single dose P188 treatment induced an increase in specific force and decreased the number of IgG positive fibers in both non-stressed and stressed muscles. P188 treatment improved the histological appearance in TA muscles under some conditions. 2-week P188 did not affect TA force. During lengthening contraction injury, it was reported that in a subset of contractions the P188 treatment group had slightly but statistically significant lower force than saline control. | Terry et al. (2014) [151] |
P188, P338 | Skeletal muscle | mdx | Pre-treatment (0.5–3 h) | 60–460 mg/kg | i.p., i.v., s.c., i.m. | Subcutaneous but not intravenous nor intraperitoneal injection of P188 significantly decreased the force loss during and after lengthening contractions of hindlimb mdx muscle and significantly decreased EBD uptake into TA myofibers post-injury. Subcutaneous delivery of PEO8000 had no protective effect. Lower dosage of intraperitoneal and intramuscular but not subcutaneous or intravenous injections of P338 shows significant protective effect. | Houang et al.(2015) [156] |
P188 | Respiratory | mdx | Q.D., 22Â weeks | 3Â mg/kg | s.c. | Chronic delivery of P188 had significant positive effects on respiratory function parameters and improved diaphragm histological parameters and caused improvement in cardiac hemodynamics of treated mdx mice | Markham et al. (2015) [217] |
Cardiomyopathy | mdx/utr −/− | Q.D., 8 weeks | 1 mg/kg | s.c. | P188 treatment slowed the loss of respiratory function and improved diaphragm histological parameters in double knockout mice | ||
diP188 diP188-CH3 diP188-(CH3)3 | Skeletal muscle | mdx | Pre-treatment (0.5–3 h) | 1000 mg/kg | i.p. | A diblock copolymer architecture confers membrane stabilization. The addition of a single hydrophobic tert-butoxy end-group to the PPO core significantly enhanced membrane protection against lengthening contractions. The less hydrophobic methoxy and hydrophilic hydroxyl end groups did not confer membrane protection in vivo. | Houang et al.(2017) [183] |