Photo Dynamic Therapy (PDT) is an approved medical technique to treat certain forms of cancer. It has been used to complement traditional anticancer modalities such as surgery, chemotherapy or radiotherapy and in certain cases, to replace these treatments. One critical parameter of PDT is the Photo Sensitizer (PS); historically, a purely organic macrocyclic tetrapyrrole-based structure. This short review surveys two recent clinical examples of metal complexes, namely TOOKAD®-Soluble and TLD-1433, which have ideal photophysical properties to act as PDT PSs. We highlight the important role played by the metal ions in the PS for PDT activity.

528 Background: Novel therapies are required for BCG-unresponsive, high risk non-muscle invasive bladder cancer. We report the interim results of a Phase II Clinical Study of Intravesical Photo Dynamic Therapy (PDT) in patients with BCG-Unresponsive Carcinoma In-Situ (CIS) with or without papillary disease. Methods: Out of a planned 125 patients, 42 patients have been enrolled and treated with two Study Treatments (Day 0 and Day 180) consisting of an intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm2) followed by activation with a 520 nm intravesical laser under general anesthesia (Study Device TLC-3200) to a total of 90 J/cm2 of laser light. The primary outcome assessed was efficacy, evaluated by Complete Response (CR), at any point in time. The secondary outcome was duration of CR at 12 months, post initial CR. A tertiary objective is safety, evaluated by the incidence and severity of Adverse Events, Grade 4 or higher that do not resolve within 450 days post treatment. Patients with a negative cystoscopy and positive cytology have been defined as indeterminate response (IR), as these patients remain under investigation for lower and upper tract urothelial carcinoma. Results: Interim analyses included the first 42 patients, along with 3 patients treated in a preceding Phase Ib NMIBC clinical study assessing the safety of TLD-1433 PDT who weretreated at the same parameters, for a total of 45 patients. Data for the primary and secondary outcomes are listed in the table.The interim clinical data demonstrates a 90 day CR of 50% and a duration of response at 360 and 450 days of 35% and 21%, respectively.There have been eight Serious Adverse Events (SAE) identified (2 Grade II (tachycardia, hematuria), 3 Grade III (acute kidney injury, cellulitis), 2 Grade IV (urosepsis, depression/anxiety) and 1 Grade V). None of the SAEs were deemed to be directly related to the PDT. Conclusions: The interim data support that treatment with Photo Dynamic Therapy provides a viable treatment option for patients with BCG unresponsive CIS (+/- papillary disease) with an acceptable ongoing safety profile. Clinical trial information: NCT03945162 . [Table: see text]

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A randomized placebo-controlled clinical trial to evaluate an adjunctive treatment modality for pain associated with knee disorders was conducted utilizing a therapeutic laser system (low energy, non-surgical).The therapeutic laser system utilized a dual wavelength, multiple diode laser cluster probe with five super-pulsed 905 nm near-infrared (NIR) laser diodes, each emitting at 40 mW average power and four continuous wave 660 nm visible (VIS) red laser diodes, each emitting at 25 mW. It was used as an adjunctive modality providing 12 treatments, three times a week to a homogeneous patient population (n=126), in combination with standardized chiropractic techniques, to evaluate effectiveness on subjects presenting with osteoarthritis and knee pain. The primary endpoint was measured by the visual analog scale (VAS) to assess pain levels on a scale of 0–10. The success criteria for an individual patient in this study were identified as an improvement of 30% or more in the VAS from baseline to 12th treatment and/or an improvement of 20% or more in the VAS from baseline to 30-day follow-up evaluation.The data obtained in the study demonstrated that the present therapeutic laser system provided significant pain relief and osteoarthritic improvements in all primary evaluation criteria, with a statistical and clinical significance of

Photodynamic therapy (PDT) is an approved procedure using a photosensitizer (PS) activated by light to selectively destroy malignant/premalignant cells. Transition metal complexes, such as Ru(II)-and Os(II)-based PSs (Theralase Technologies Inc., Ontario. Canada), are activated in a wide range of wavelengths, are resistant to photobleaching and have a high singlet oxygen quantum yield and ability to produce cytotoxic reactive oxygen species (ROS). Their design allows fine-tuning of the photophysical and photochemical properties. They demonstrate Type I and II photoreactions, and some are activated in hypoxia. High PDT potency and activation under NIR light and even X-ray may provide an advantage over the approved PSs. Their ability to associate with transferrin (Tf) as an endogenous delivery system increases photobleaching resistance, ROS production, selective cellular uptake, and PDT efficacy in combination with a decreased systemic toxicity. This makes these PSs attractive for systemic therapy of recurrent/progressive cancers. Their PDT efficacy has been demonstrated in various in vitro and in vivo clinically relevant models. The unique properties of the mentioned PSs allow bypassing such limitations of PDT as low specific uptake ratio, insufficiently broad absorption band, and low efficacy in hypoxia. One of these PSs (TLD-1433) was successful against non-muscle invasive urinary bladder cancer unresponsive to contemporary anticancer therapies. extensive hypoxic regions, which are also associated with the tumor aggressiveness [15,16]. Although hypoxic regions still can be treated (at a slower rate) by application of fractionated exposure or inducing reperfusion [17,18], hypoxia severely decreases PDT efficacy [19]. Together with the limited light penetration, this is another reason why PDT in its current state is usually limited to relatively superficial lesions. This problem could be bypassed by PSs employing photoreactions that have little or no dependency on oxygen.Considering the said above, an advanced PS should have the ability for targeted delivery; penetration through the blood-brain barrier (BBB) and blood-tumor cell barrier (BTCB); activation by a wide range of wavelengths, including NIR light; and employing of different types of photoreactions enabling induction of immune responses to tumor antigens. Solubility in water and/or saline is a great asset for a successful PS as it makes its delivery both easier and safer, without the use of excipients with potential toxicity/side effects on their own.Metal-based coordination complexes are among the obvious candidates to satisfy these requirements. Specifically, transition metal complexes possess a wide range of metal oxidation states and the complex geometries [5,20]. These complexes (e.g., Ru(II) polypyridyl complexes) are of increasing interest as PSs in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT) [21]. Importantly, they can have their properties fine-tuned by choosing the central metal and organic ligands (such as bipyrid...