- In previous research, an intravesical semisynthetic glycosaminoglycan ether (SAGE), designated GM-0111, showed increased anti-inflammatory effects in mice compared with pentosan sulfate
- To improve bladder residence time, SAGE GM-0111 was combined with a silk-elastinlike protein polymer (SELP); the solution can be injected through a catheter but then forms a gel within the bladder
- Two SAGE–SELP solutions were tested; in both cases, SAGE GM-0111 was released for 24 hours and provided analgesia for at least that long
- Administering SAGE GM-0111 to the bladder visibly reduced inflammation and ulceration in the urothelium
For treatment of interstitial cystitis and painful bladder syndrome (IC/PBS), the only approved drug in the U.S. is oral pentosan sulfate. As a glycosaminoglycan, its proposed mode of action is to restore the mucosal barrier function within the bladder and prevent irritating solutes from reaching the bladder wall.
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However, pentosan sulfate has limited efficacy, and it has no analgesic and anti-inflammatory effects. Patients treated with intravesical glycosaminoglycans (hyaluronic acid or heparin) may have better pain relief, but it is still modest, and the effect can be delayed for three to six months.
Intravesical delivery of semisynthetic glycosaminoglycan ethers (SAGE) has the potential to overcome the shortcomings of current glycosaminoglycans by offering both mucosal restoration and potent analgesic and anti-inflammatory effects. In previous research published in the International Forum of Allergy & Rhinology, Siam Oottamasathien, MD, director of Pediatric Urology Basic Science Research at Mass General Hospital for Children, and colleagues found that a SAGE they designated GM-0111 showed increased anti-inflammatory effects compared with pentosan sulfate in a mouse model of rhinosinusitis.
The problem remains, though, that patients can typically tolerate intravesical solutions for only 60 to 90 minutes. To enhance SAGE GM-0111, the researchers have been experimenting with two temperature-responsive silk-elastinlike protein polymer (SELP) delivery systems. SAGE–SELP solutions mimic the natural components of the mucous membrane within the bladder and transition into a gel that improves retention of the SAGE drug.
In Biomaterials, Dr. Oottamasathien and his colleagues at the University of Utah report that in a mouse model of IC/PBS, adding SELP to SAGE GM-0111 resulted in retention of the drug for 24 hours, resulting in a sustained analgesic effect and reduced inflammation.
The researchers evaluated four polymer systems:
- SELP 415K and SELP 815K, which have minor differences in polymer architecture. In vitro, both SELPs showed a controlled release of SAGE GM-0111 for 24 hours in simulated urine
- PLGA-PEG-PLGA and poloxamer 407, two other polymer systems that form gels in situ. In simulated urine, they dumped over 80% of their drug payload within one minute
The researchers induced IC/PBS in female C57BL/6 mice using LL-37, the only human cathelicidin, which is found in the urine of IC/PBS patients. One hour later, groups of mice received SAGE GM-0111 plus SELP 415K, SELP 815 K, PLGA-PEG-PLGA, poloxamer 407 or saline. Other groups received one of the four investigational polymers without SAGE. A last group of mice was catheterized but received no treatment (reference controls).
- The reference mice tended to have one or two large voiding events in the corners of their cages, as expected
- SELP 815K gelled relatively quickly and stiffly, forming a free-floating gel mass within the bladder. This led to reduced capacity and potential bladder outlet obstruction—frequent small urination events in the center of the cage indicated an increased sense of urgency
- SELP 415K gelled more slowly and had a more elastic character. Rather than being a floating mass, it was observed as a tight elastic film on the urothelium where SAGE could accumulate. It demonstrated less impact on urination than SELP 815K did
- Neither PLGA-PEG-PLGA nor poloxamer 407 significantly altered the frequency or volume of urination. No residual PLGA-PEG-PLGA or poloxamer 407 was observed in the bladder after administration, so the lack of effect on urination was probably due to rapid clearance from the bladder
Pain response was assessed by stimulating the suprapubic area of the mice with Von Frey filaments. The induction of IC/PBS with LL-37 increased the maximal pain response rate by 250% compared with the reference controls.
Twenty-four hours after administration, all solutions that contained SAGE GM-0111, including saline, demonstrated greater analgesic effects than polymer solutions without SAGE. The most effective was SAGE–SELP 415K, which reduced the pain response by 56% compared with saline. The second most effective was SAGE–SELP 815K.
The researchers attribute the superior analgesic effects of the SELP polymers to their ability to increase retention of SAGE in the bladder.
On visual inspection, mouse bladders clearly showed swelling, erythema and ulceration 24 hours after administration of LL-37. The addition of SAGE GM-0111 to polymer solutions drastically reduced these signs of inflammation. In fact, in many cases, the bladders of SAGE-treated mice were visually indistinguishable from those of the reference mice. Histology substantiated these observations.
The ability of SELP 415K and 815K to extend drug release to 24 hours is a significant step forward for non-device–based intravesical drug delivery. The clinical relevance of mouse modeling is limited in the field of urodynamics, but this paper lays the groundwork for future research in large animals and alternative models of IC/PBS.
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