Fimaporfin
(Synonyms: TPCS2a) 目录号 : GC61876
Fimaporfin (TPCS2a) 是一种定位在内体/溶酶体的光敏剂。
Cas No.:1443547-43-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Fimaporfin (TPCS2a) is an endosomal/lysosomal-localizing photosensitizer[1].
The endosomal/lysosomal localizing photosensitizer Fimaporfin (0.35 µg/ml) is used in the drug delivery technology photochemical internalization (PCI) in combination with drugs that usually are trapped in endosomes and/or lysosomes[1].
References:
[1]. Kaja Lund, et al. 5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105-saporin. J Exp Clin Cancer Res. 2017 Dec 19;36(1):187.
| Cas No. | 1443547-43-0 | SDF | |
| 别名 | TPCS2a | ||
| Canonical SMILES | O=S(C1=CC=C(/C2=C3C=CC(/C(C4=CC=C(S(=O)(O)=O)C=C4)=C5C=C/C(N/5)=C(C6=CC=CC=C6)/C(C=C/7)=NC7=C(C8=CC=CC=C8)/C9=CC=C2N9)=N\3)C=C1)(O)=O | ||
| 分子式 | C44H30N4O6S2 | 分子量 | 774.86 |
| 溶解度 | 储存条件 | Store at -20°C | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.2906 mL | 6.4528 mL | 12.9056 mL |
| 5 mM | 0.2581 mL | 1.2906 mL | 2.5811 mL |
| 10 mM | 0.1291 mL | 0.6453 mL | 1.2906 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Light-controlled elimination of PD-L1+ cells
J Photochem Photobiol B 2021 Dec;225:112355.PMID:34768077DOI:10.1016/j.jphotobiol.2021.112355.
The programmed death ligand-1 (PD-L1), also known as CD274 or B7-H1, is mainly expressed on cancer cells and/or immunosuppressive cells in the tumor microenvironment (TME) and plays an essential role in tumor progression and immune escape. Immune checkpoint inhibitors (ICIs) of the PD-1/PD-L1 axis have shown impressive clinical success, however, the majority of the patients do not respond to immune checkpoint therapy (ICT). Thus, to overcome ICT resistance there is a high need for potent and novel strategies that simultaneously target both tumor cells and immunosuppressive cells in the TME. In this study, we show that the intracellular light-controlled drug delivery method photochemical internalization (PCI) induce specific and strongly enhanced cytotoxic effects of the PD-L1-targeting immunotoxin, anti-PD-L1-saporin (Anti-PDL1-SAP), in the PD-L1+ triple-negative breast cancer MDA-MB-231 cell line, while no enhanced efficacy was obtained in the PD-L1 negative control cell line MDA-MB-453. Using fluorescence microscopy, we reveal that the anti-PD-L1 antibody binds to PD-L1 on the surface of the MDA-MD-231 cells and overnight accumulates in late endosomes and lysosomes where it co-localizes with the PCI photosensitizer Fimaporfin (TPCS2a). Moreover, light-controlled endosomal/lysosomal escape of the anti-PD-L1 antibody and Fimaporfin into the cytosol was obtained. We also confirm that the breast MDA-MB-468 and the prostate PC-3 and DU-145 cancer cell lines have subpopulations with PD-L1 expression. In addition, we show that interferon-gamma strongly induce PD-L1 expression in the per se PD-L1 negative CT26.WT cells and enhance the PD-L1 expression in MC-38 cells, of which both are murine colon cancer cell lines. In conclusion, our work provides an in vitro proof-of-concept of PCI-enhanced targeting and eradication of PD-L1 positive immunosuppressive cells. This light-controlled combinatorial strategy has a potential to advance cancer immunotherapy and should be explored in preclinical studies.
Photochemical Internalization of Gemcitabine Is Safe and Effective in Locally Advanced Inoperable Cholangiocarcinoma
Oncologist 2022 Jun 8;27(6):430-e433.PMID:35675633DOI:10.1093/oncolo/oyab074.
Background: Photochemical internalization (PCI) is a novel technology for light-induced enhancement of the local therapeutic effect of cancer drugs, utilizing a specially designed photosensitizing molecule (Fimaporfin). The photosensitizing molecules are trapped in endosomes along with macromolecules or drugs. Photoactivation of Fimaporfin disrupts the endosomal membranes so that drug molecules are released from endosomes inside cells and can reach their therapeutic target in the cell cytosol or nucleus. Compared with photodynamic therapy, the main cytotoxic effect with PCI is disruption of the endosomal membrane resulting in delivery of chemotherapy drug, and not to the photochemical reactions per se. In this study we investigated the effect of PCI with gemcitabine in patients with inoperable perihilar cholangiocarcinoma (CCA). Methods: The in vitro cytotoxic effect of PCI with gemcitabine was studied on two CCA-derived cell lines. In a Fimaporfin dose-escalation phase I clinical study, we administered PCI with gemcitabine in patients with perihilar CCA (n = 16) to establish a safe and tolerable Fimaporfin dose and to get early signals of efficacy. The patients enrolled in the study had tumors in which the whole length of the tumor could be illuminated from the inside of the bile duct, using an optical fiber inserted via an endoscope (Fig. 1). Fimaporfin was administered intravenously at day 0; gemcitabine (i.v.) and intraluminal biliary endoscopic laser light application on day 4; followed by standard gemcitabine/cisplatin chemotherapy. Results: Preclinical experiments showed that PCI enhanced the effect of gemcitabine. In patients with CCA, PCI with gemcitabine was well tolerated with no dose-limiting toxicities, and no unexpected safety signals. Disease control was achieved in 10 of 11 evaluable patients, with a clearly superior effect in the two highest dose groups. The objective response rate (ORR) was 42%, including two complete responses, while ORR at the highest dose was 60%. Progression-free survival at 6 months was 75%, and median overall survival (mOS) was 15.4 months, with 22.8 months at the highest Fimaporfin dose. Conclusion: Photochemical internalization with gemcitabine was found to be safe and resulted in encouraging response and survival rates in patients with unresectable perihilar CCA.
Inhibiting autophagy increases the efficacy of low-dose photodynamic therapy
Biochem Pharmacol 2021 Dec;194:114837.PMID:34780750DOI:10.1016/j.bcp.2021.114837.
Rupture and permeabilization of endocytic vesicles can be triggered by various causes, such as pathogenic invasions, amyloid proteins, and silica crystals leading to cell death and degeneration. A cellular quality control process, called lysophagy was recently described to target damaged lysosomes for autophagic sequestration within isolation membranes in order to protect the cell from the consequences of lysosomal leakage. This protective process, however, might interfere with treatment conditions, such as photodynamic therapy (PDT) and the intracellular drug delivery method photochemical internalization (PCI). PCI-induced permeabilization of endosomes and lysosomes is purposely triggered to release drugs that are sequestered in these organelles into the cytosol in order to synergistically kill cancer cells. Here, we show that photochemical treatment with the PCI-photosensitizer TPCS2a/Fimaporfin results in both induction of autophagy and inhibition of the autophagic flux. The autophagic response is accompanied by recruitment of ubiquitin (Ubq), p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3) to damaged vesicles, marked by Galectin 3 (Gal3). Furthermore, ultrastructural analysis revealed a homogenously thick p62-positive layer surrounding these permeabilized vesicles. Although p62 seems to be important during the selective autophagic sequestration, we show that its presence is not essential for the effective removal of damaged vesicles or the recovery of the lysosomal content. An active autophagic response and the presence of p62, however, is important for cancer cells to survive low-dose TPCS2a-PDT. Thus, targeting both p62 and autophagy together and independently, in a light-controlled/PCI based delivery of cancer therapeutics could increase the effectiveness of the treatment regime.
Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers
Front Immunol 2021 Jan 8;11:576756.PMID:33488576DOI:10.3389/fimmu.2020.576756.
Background and aims: Photochemical internalization (PCI) is a technology for inducing release of endocytosed antigens into the cell cytosol via a light-induced process. Preclinical experiments have shown that PCI improves MHC class I antigen presentation, resulting in strongly enhanced CD8+ T-cell responses to polypeptide antigens. In PCI vaccination a mixture of the photosensitizing compound Fimaporfin, vaccine antigens, and an adjuvant is administered intradermally followed by illumination of the vaccination site. This work describes an open label, phase I study in healthy volunteers, to assess the safety, tolerability, and immune response to PCI vaccination in combination with the adjuvant poly-ICLC (Hiltonol) (ClinicalTrials.gov Identifier: NCT02947854). Methods: The primary objective of the study was to assess the safety and local tolerance of PCI mediated vaccination, and to identify a safe Fimaporfin dose for later clinical studies. A secondary objective was to analyze the immunological responses to the vaccination. Each subject received 3 doses of HPV16 E7 peptide antigens and two doses of Keyhole Limpet Hemocyanin (KLH) protein. A control group received Hiltonol and vaccine antigens only, whereas the PCI groups in addition received Fimaporfin + light. Local and systemic adverse effects were assessed by standard criteria, and cellular and humoral immune responses were analyzed by ELISpot, flow cytometry, and ELISA assays. Results: 96 healthy volunteers were vaccinated with Fimaporfin doses of 0.75-50 µg. Doses below 17.5 µg were safe and tolerable, higher doses exhibited local tolerability issues in some study subjects, mainly erythema, and pain during illumination. There were few, and only mild and expected systemic adverse events. The employment of PCI increased the number of subjects exhibiting a T-cell response to the HPV peptide vaccine about 10-fold over what was achieved with the antigen/Hiltonol combination without PCI. Moreover, the use of PCI seemed to result in a more consistent and multifunctional CD8+ T-cell response. An enhancement of the humoral immune response to KLH vaccination was also observed. Conclusions: Using PCI in combination with Hiltonol for intradermal vaccination is safe at Fimaporfin doses below 17.5 µg, and gives encouraging immune responses to peptide and protein based vaccination.
High aldehyde dehydrogenase activity does not protect colon cancer cells against TPCS2a-sensitized photokilling
Photochem Photobiol Sci 2020 Mar 1;19(3):308-312.PMID:32108197DOI:10.1039/c9pp00453j.
Aldehyde dehydrogenases (ALDH) are detoxifying enzymes that are upregulated in cancer stem cells (CSCs) and may cause chemo- and ionizing radiation (IR) therapy resistance. By using the ALDEFLUOR assay, CD133 + human colon cancer cells HT-29, were FACSorted into three populations: ALDHbright, ALDHdim and unsorted (bulk) and treated with chemo-, radio- or photodynamic therapy (PDT) using the clinical relevant photosensitizer disulfonated tetraphenyl chlorin (TPCS2a/Fimaporfin). Here we show that there is no difference in cytotoxic responses to TPCS2a-PDT in ALHDbright, ALDHdim or bulk cancer cells. Likewise, both 5-FU and oxaliplatin chemotherapy efficacy was not reduced in ALDHbright as compared to ALDHdim cancer cells. However, we found that ALHDbright HT-29 cells are significantly less sensitive to ionizing radiation compared to ALDHdim cells. This study demonstrates that the cytotoxic response to PDT (using TPCS2a as photosensitizer) is independent of ALDH activity in HT-29 cancer cells. Our results further strengthen the use of TPCS2a to target CSCs.