Silk-elastinlike copolymers enhance bioaccumulation of semisynthetic glycosaminoglycan ethers for prevention of radiation induced proctitis.

Radiation-induced proctitis (RIP) is a debilitating adverse event that occurs commonly during lower abdominal radiotherapy. The lack of prophylactic treatment strategies leads to diminished patient quality of life, disruption of radiotherapy schedules, and limitation of radiotherapy efficacy due to dose-limiting toxicities. Semisynthetic glycosaminoglycan ethers (SAGE) demonstrate protective effects from RIP. However, low residence time in the rectal tissue limits their utility. We investigated controlled delivery of GM-0111, a SAGE analogue with demonstrated efficacy against RIP, using a series of temperature-responsive polymers to compare how distinct phase change behaviors, mechanical properties and release kinetics influence rectal bioaccumulation. Poly(lactic acid)-co-(glycolic acid)-block-poly(ethylene glycol)-block-poly(lactic acid)-co-(glycolic acid) copolymers underwent macroscopic phase separation, expelling >50% of drug during gelation. Poloxamer compositions released GM-0111 cargo within 1 h, while silk-elastinlike copolymers (SELPs) enabled controlled release over a period of 12 h. Bioaccumulation was evaluated using fluorescence imaging and confocal microscopy. SELP-415K, a SELP analogue with 4 silk units, 15 elastin units, and one elastin unit with lysine residues in the monomer repeats, resulted in the highest rectal bioaccumulation. SELP-415K GM-0111 compositions were then used to provide localized protection from radiation induced tissue damage in a murine model of RIP. Rectal delivery of SAGE using SELP-415K significantly reduced behavioral pain responses, and reduced animal mass loss compared to irradiated controls or treatment with traditional delivery approaches. Histological scoring showed RIP injury was ameliorated for animals treated with GM-0111 delivered by SELP-415K. The enhanced bioaccumulation provided by thermoresponsive SELPs via a liquid to semisolid transition improved rectal delivery of GM-0111 to mice and radioprotection in a RIP model.

Unilateral open extravesical ureteral reimplanation with contralateral dextronomer/hyaluronic acid injection performed as an outpatient therapy.

INTRODUCTION: Historically, patients with unilateral high-grade vesicoureteral reflux (VUR) and contralateral low-grade or resolved VUR have been treated with bilateral intravesical ureteral reimplantation, which requires postoperative admission. If the high-grade VUR side is treated alone, then the contralateral side is at risk of developing recurrent or worsening VUR. Bilateral subureteric injection of dextronomer/hyaluronic acid (DHA) is another option that can be performed as an outpatient therapy, but a single injection is less effective for high-grade VUR. OBJECTIVE: The safety and efficacy of an outpatient combination of open extravesical ureteral reimplantation (EVUR) and contralateral DHA injection were investigated. STUDY DESIGN: A retrospective review of children who had concomitant EVUR and subureteric injection of DHA between January 2005 and December 2015 was performed. Exclusion criteria were diagnosis other than VUR, repeat procedures, and patients with no follow-up. Patient characteristics, postsurgical complications, and follow-up imaging were evaluated. Febrile urinary tract infection (fUTI) was defined as ≥50,000 Colony Forming Units (CFU) of an organism from clean-catch or catheterized urine and temperature ≥ 101.5 F. Clinical success is defined as no fUTI for 1 year after the initial operation. Univariate analyses were used to identify risk factors for treatment failure. RESULTS: A total of 117 patients met inclusion criteria. Mean age at surgery was 6.0 years, and 85% were female. The mean pre-operative grade of VUR was 3.3 on the EVUR side and 0.6 on the contralateral side (42% resolved before treatment). Median follow-up was 12.2 months (interquartile range, 3.1-25.4). Sixteen patients (14%) had documented fUTI within 1 year, with a clinical success rate of 86%. Of these, five had a postoperative imaging showing resolution of VUR, increasing overall success to 91%. Postoperative fUTI was more common in patients with pre-operative bowel and bladder dysfunction (BBD) (P = 0.003), but this was not associated with a higher reoperation rate (P = 0.168). There were 11 total complications, with three grade 3 complications. DISCUSSION: This study is the first to report safety and outcomes of EVUR and contralateral DHA injection for patients with high-grade VUR with contralateral low-grade or resolved VUR. It was shown that it is an effective and safe treatment that can be performed as an outpatient therapy. Limitations to this study include the retrospective design and the clinical definition of success that is used in a cohort of patients from across the mountain west region without routine postoperative voiding cystourethrogram. CONCLUSION: Extravesical ureteral reimplantation and contralateral DHA injection can safely be performed as an outpatient therapy and are effective in the treatment of higher grade VUR with contralateral low-grade or resolved VUR. Treatment failure is more likely in patients with BBD.