vascular-acting photosensitizer

Padeliporfin mediates tumour-specific cytotoxicity. It works to destroy target cells through the release of reactive oxygen species in response to an exposure to laser light radiation delivered at a specific wavelength. Padeliporfin causes vascular shutdown and activation of an immune response in the target tissue.

In preclinical studies in animal models, padeliporfin-mediated photosensitization caused occlusion of the full tumour vasculature in a few minutes of treatment. Padeliporfin remains confined within the circulation even at high doses with minimal extravasation: reactive oxygen species generated upon laser activation are contained in the vasculature and do not directly kill tumour cells.

---

In the intention-to-treat population (n=81), the proportion of patients with negative biopsies at month 12 was 74% (60/81 patients; 95% CI: 63.1%,83.2%). In the per-protocol population, the proportion was 79% (58/73 patients; 95% CI: 68.4%,88.0%). Questionnaire results indicated a slight improvement in urinary function and limited deterioration in sexual function. No difference in QoL was observed over time. A total of 42/81 (52%) patients reported mild or moderate and 4 of 81 (4.9%) experienced serious AE, all resolved without sequelae. No phototoxicity, cardiovascular event, fistula or prolonged urinary incontinence, secondary cancer or death was reported. Conclusions: Results support the efficacy, safety, and QoL associated with padeliporfin focal treatment for low/intermediate risk localized PCa.[1]

Objectives: To explore the proportion of patients with higher risk localized prostate cancer (PCa) that would become safely biopsy negative 12 months after non-thermal focal therapy with padeliporfin vascular-targeted photodynamic therapy (VTP). Methods: Multicenter study in a scenario of prostate-specific antigen (PSA) ≤20ng/ml and variable PCa target volumes Gleason pattern 3 or low-volume secondary Gleason pattern 4, all patients received VTP, consisting of intravenous 4mg/kg padeliporfin activated by light-diffusing fibers in the prostate. The prostate was biopsied at baseline, months 6 and 12, PSA, patient-reported functional outcomes and quality of life (QoL) questionnaires were recorded at baseline, months 3, 6, and 12 and adverse events (AE) throughout the study.[1]

Absorption, Distribution and Excretion
After intravenous bolus injection at a dose of 6 mg/kg into healthy mice, the Cmax of padeliporfin was about 52 mg/L, with a Tmax of two minutes.
In healthy subjects, urinary excretion of padeliporfin was very low, accounting for less than 0.2% of the dose. Fecal elimination is a suspected predominant route of elimination.
In healthy men receiving 1.25 to 15 mg/kg of padeliporfin di-potassium, the mean volume of distribution (V_d) ranged from 0.064 to 0.279 L/kg. In patients with localized prostate cancer treated with 2 and 4 mg/kg of padeliporfin di-potassium, the mean V_d ranged from 0.09 to 0.10 L/kg. Upon administration, padeliporfin remain confined within the circulation even at high doses, with minimal extravasation to other tissues.
Following administration of 1.25-15 mg/kg of padeliporfin di-potassium in healthy men, clearance of padeliporfin di-potassium ranged from 0.0245 to 0.088 L/h/kg. In patients with localised prostate cancer treated with 4 mg/kg and 2 mg/kg of padeliporfin di-potassium, clearance was 0.04 L/h/kg and 0.06 L/h/kg, respectively.

---

Metabolism / Metabolites
In human liver microsomes and S9 fractions, padeliporfin underwent minimal metabolism. No metabolites of padeliporfin have been identified yet as a radiolabeled study has not been performed.

---

Biological Half-Life
The estimated half-life is 1.19 hrs ± 0.08 at 4 mg/kg of padeliporfin di-potassium.

Protein Binding
Padeliporfin di-potassium is 99% bound to human plasma proteins. Padeliporfin binds to high-density proteins, including serum albumin, but binds poorly to low-level density lipoproteins and high-density lipoproteins.

[1]. Expanding indication of padeliporfin (WST11) vascular-targeted photodynamic therapy: results of prostate cancer Latin-American multicenter study. Actas Urol Esp (Engl Ed) . 2018 Dec;42(10):632-638.

Padeliporfin is a water-soluble chlorophyll derivative and cytotoxic photosensitizer used for vascular-targeted photodynamic therapy for malignancies. Vascular-targeted photodynamic therapy (VTP), or vascular targeted photochemotherapy, is a focal treatment for localized prostate cancer. It aims to destroy only cancerous lesions of the prostate, rather than ablating the entire prostate gland. Padeliporfin was first approved by the European Commission on November 10, 2017, for the treatment of low-risk prostate cancer in adults meeting certain clinical criteria.
Padeliporfin is a vascular-acting photosensitizer consisting of a water-soluble, palladium-substituted bacteriochlorophyll derivative with potential antineoplastic activity. Upon administration, paldeliporfin is activated locally when the tumor bed is exposed to low-power laser light; reactive oxygen species (ROS) are formed upon activation and ROS-mediated necrosis may occur at the site of interaction between the photosensitizer, light and oxygen. Vascular-targeted photodynamic therapy (VTP) with padeliporfin may allow tumor-site specific cytotoxicity while sparing adjacent normal tissues.

---

Drug Indication
Padeliporfin is indicated for the treatment of adults with previously untreated, unilateral, low-risk, adenocarcinoma of the prostate with a life expectancy greater than or equal to 10 years. Patients must meet the following criteria: clinical stage T1c or T2a; Gleason Score ≤ 6, based on high-resolution biopsy strategies; PSA ≤ 10 ng/mL; and 3 positive cancer cores with a maximum cancer core length of 5 mm in any one core or 1-2 positive cancer cores with ≥ 50 % cancer involvement in any one core or a PSA density ≥ 0.15 ng/mL/cm3.
Tookad is indicated as monotherapy for adult patients with previously untreated, unilateral, low risk, adenocarcinoma of the prostate with a life expectancy ≥ 10 years and: Clinical stage T1c or T2a; Gleason Score ≤ 6, based on high-resolution biopsy strategies; PSA ≤ 10 ng/mL; 3 positive cancer cores with a maximum cancer core length of 5 mm in any one core or 1-2 positive cancer cores with ≥ 50 % cancer involvement in any one core or a PSA density ≥ 0. 15 ng/mL/cm³.

---

Mechanism of Action
Vascular-targeted photodynamic therapy (VTP), or vascular targeted photochemotherapy, is a focal treatment for localized prostate cancer. VTP involves the process of light activation of photosensitizer localized in the target tissue, which produces reactive oxygen species that work to destroy target cells. Padeliporfin is retained within the vascular system. When activated with 753 nm wavelength laser light, padeliporfin triggers a photochemical reaction that generates oxygen radicals (hydroxyl radical, superoxide radical), thereby causing local hypoxia of the target tissue. Nitric oxide radicals are also released, resulting in transient arterial vasodilatation that triggers the release of the vasoconstrictor, endothelin-1. Rapid consumption of the nitric oxide radicals by oxygen radicals leads to the formation of reactive nitrogen species (RNS) including peroxynitrite, in parallel to arterial constriction. Impaired deformability enhances erythrocyte aggregability and formation of blood clots at the interface of the arterial supply of the target tissue, leading to occlusion of the tumour vasculature, or "vascular shutdown." This effect is enhanced by RNS-induced endothelial cell apoptosis and initiation of self-propagated tumour cells necrosis through peroxidation of their membrane.

C37H43N5O9S-2.PD+2

840.250420000001

837.166

C, 48.49; H, 4.51; K, 8.53; N, 7.64; O, 15.71; Pd, 11.61; S, 3.50

759457-82-4

759457-82-4; 698393-30-5 (potassium);

145712321

Typically exists as solid at room temperature

1.595

1

13

10

53

1870

4

[Pd+2].OC(CC[C@H]1[C@H](C)C2=NC1=C(C1[N-]C(C=C3N=C(C=C4[N-]C(=C2)C(C)=C4C(=O)C)[C@H](C)[C@H]3CC)=C(C)C=1C(NCCS(=O)(O)=O)=O)CC(OC)=O)=O

MZRDSGWDVDESRC-VNWQTDIGSA-J

InChI=1S/C37H45N5O9S.Pd/c1-8-22-17(2)25-16-30-33(21(6)43)19(4)27(40-30)14-26-18(3)23(9-10-31(44)45)35(41-26)24(13-32(46)51-7)36-34(37(47)38-11-12-52(48,49)50)20(5)28(42-36)15-29(22)39-25;/h14-18,22-23H,8-13H2,1-7H3,(H5,38,39,40,41,42,43,44,45,47,48,49,50);/q;+2/p-4/t17-,18+,22-,23+;/m1./s1

3-[(2S,3S,12R,13R)-8-acetyl-13-ethyl-20-(2-methoxy-2-oxoethyl)-3,7,12,17-tetramethyl-18-(2-sulfonatoethylcarbamoyl)-2,3,12,13-tetrahydroporphyrin-22,24-diid-2-yl]propanoate;palladium(2+)

padeliporfin; Padeliporfin [INN]; EEO29FZT86; WST11 compound; Stakel; WST-11; UNII-EEO29FZT86; WST 1;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)