Evaluation of a Ruthenium coordination complex as photosensitizer for PDT of bladder cancer: Cellular response, tissue selectivity and in vivo response

Abstract

TLD1433, a Ru(II) polypyridyl complex, was recently introduced. It can be activated in the 520 to 540 nm range. Here we report on the use of TLD1433 for the treatment of bladder carcinomas in vitro and in an in vivo orthotopic model. The electrostatic properties of the normal urothelium vs a tumor compromised urothelium provide for a high selective uptake ratio. In vitro, a 1000 difference in the LD 50 between dark and 22.5 J cm −2 irradiation at 530 nm was achieved for two bladder cell lines (T24 and AY-27). In dogs and rats the plasma concentration for TLD1433 was below 100 ng kg −1 at 72 hours following intravenous injection at a dose of up to 3.5 mg kg −1 and below 10 ng kg −1 following intrabladder instillation for 1 hour at a concentration of 6 mg mL −1. Successful tumor necrosis close to 1.5 mm in depth was achieved.

Minimal required PDT light dosimetry for nonmuscle invasive bladder cancer

“…In conclusion, the preclinical studies 26 showed that TLD-1433 for NMIBC presents with a considerable SUR of 192. PDT treatment selectivity needs to ensure the threshold for the tumor being exceeded across the bladder wall but not for the normal urothelium.…”

“…PDT treatment selectivity needs to ensure the threshold for the tumor being exceeded across the bladder wall but not for the normal urothelium. The worst-case estimate for the threshold values reported 26 one that needs 13.2 times more photons to be absorbed in the tumor compared to the urothelium and detrusor muscle, respectively, to achieve selectivity. Selectivity between the tumor and the muscle is independent of light attenuation across the bladder mucosa, whereas selectivity between tumor and urothelium needs to consider the differences in fluence across the mucosa.…”

“…Excitation light delivery was terminated when the average of the responding sensors reached the target radiant exposure of 90 AE 9 J • cm −2 , shown in animal experiments to be a safe exposure resulting in tissue necrosis. 26…”

“…The resulting selective uptake ratio (SUR) is 192. 26 It is reasonable to assume an equally big SUR for human cases as the urothelium is positively charged, causing an electrostatic repulsion of the photosensitizer. Using the AY-27 rat tumor model, the sensitivity of normal urothelium, muscle tissue, and the tumor was defined for TLD1433-mediated PDT employing the photodynamic threshold concept in vivo.…”

Bis[pyrrolyl Ru(ii)] triads: a new class of photosensitizers for metal–organic photodynamic therapy

“…16,48,[53][54][55][56][57][58][59][60][61] Our TLD1433 is one example, which is a bisheteroleptic Ru(II) complex based on the a-terthienylappended imidazo [4,5-f] [1,10]phenanthroline (IP-3T) ligand that generates 1 O 2 with almost unity efficiency. 16,17,48,[62][63][64][65][66] TLD1433 is the rst Ru(II) complex to enter a human clinical trial and is being evaluated in a Phase 2 clinical trial for treating non-muscle invasive bladder cancer with PDT (Clinicaltrials.gov identier: NCT03945162). 16,17,66 Our ongoing interest in exploring the photoreactivity of Ru(II) metal-organic systems, including TLD1433, inspired the present study.…”