Minimal required PDT light dosimetry for nonmuscle invasive bladder cancer

Abstract

Significance: Photodynamic therapy (PDT) could become a treatment option for nonmuscle invasive bladder cancer when the current high morbidity rate associated with red light PDT and variable PDT dose can be overcome through a combination of intravesical instillation of the photosensitizer and the use of green light creating a steep PDT dose gradient. Aim: To determine how a high PDT selectivity can be maintained throughout the bladder wall considering other efficacy determining parameters, in particular, the average optical properties of the mucosal layer governing the fluence rate multiplication factor, as well as the bladder shape and the position of the emitter in relationship to the bladder wall. Approach: We present three irradiance monitoring systems and evaluate their ability to enable selective bladder PDT considering previously determined photodynamic threshold values for the bladder cancer, mucosa and urothelium in a preclinical model, and the photosensitizer's specific uptake ratio. Monte Carlo-based light propagation simulations performed for six human bladders at the time of therapy for a range of tissue optical properties. The performance of one irradiance sensing device in a clinical phase 1B trial is presented to underline the impact of irradiance monitoring, and it is compared to the Monte Carlo-derived dose surface histogram. Results: Monte Carlo simulations showed that irradiance monitoring systems need to comprise at least three sensors. Light scattering inside the bladder void needs to be minimized to prevent increased heterogeneity of the irradiance. The dose surface histograms vary significantly depending on the bladder shape and bladder volume but are less dependent on tissue optical properties. Conclusions: We demonstrate the need for adequate irradiance monitoring independent of a photosensitizer's specific uptake ratio.

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.…”

“…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. Herein, we explore the bis[Ru(II)-pyrrolide] scaffold, a metal-organic-metal triad, to push the envelope for achieving unprecedented in vitro PDT potency with 3 IL excited states.…”

“… 16 , 48 , 53 – 61 Our TLD1433 is one example, which is a bis-heteroleptic Ru( ii ) complex based on the α-terthienyl-appended imidazo[4,5- f ][1,10]phenanthroline (IP-3T) ligand that generates 1 O 2 with almost unity efficiency. 16 , 17 , 48 , 62 – 66 TLD1433 is the first 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 identifier: NCT03945162). 16 , 17 , 66 …”

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 bis-heteroleptic Ru(II) complex based on the -terthienyl-appended imidazo [4,5f] [1,10]phenathroline (IP-3T) ligand that generates 1 O2 with almost unity efficiency. 16,17,48,[62][63][64][65][66] TLD1433 is the first Ru(II) complex to enter a human clinical trial and is being evaluated in a Phase 2 clinical trial for treating nonmuscle invasive bladder cancer with PDT (Clinicaltrials.gov identifier: NCT03945162). 16,17,66 Our ongoing interest in exploring the photoreactivity of Ru(II) metal-organic systems, including TLD1433, inspired the present study.…”

“…16,17,48,[62][63][64][65][66] TLD1433 is the first Ru(II) complex to enter a human clinical trial and is being evaluated in a Phase 2 clinical trial for treating nonmuscle invasive bladder cancer with PDT (Clinicaltrials.gov identifier: NCT03945162). 16,17,66 Our ongoing interest in exploring the photoreactivity of Ru(II) metal-organic systems, including TLD1433, inspired the present study. Herein, we explore the bis[Ru(II)-pyrrolide] scaffold, a metal-organic-metal triad, to push the envelope for achieving unprecedented in vitro PDT potency with 3 IL excited states.…”