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| ln Vitro |
Protohypericin emits red fluorescence, which allows for the visualization of its intratumoral biodistribution at a microscopic level.
In A549 human NSCLC tumor-bearing nude mice, higher prohypericin uptake appeared in necrotic tumor regions compared to viable tumor regions, as observed by fluorescence microscopy. The necrotic/viable tumor fluorescence intensity ratios were 1.1, 28.8, and 41.7 at 4 h, 24 h, and 120 h post-administration, respectively. At the early time point (4 h), fluorescence intensity was comparable in both necrotic and viable tumor, but the ratio increased at 24 h and 120 h. [2] |
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| ln Vivo |
In A549 tumor-bearing nude mice, \(^{131}\)I-prohypericin (185 MBq/Kg) combined with the vascular disrupting agent combretastatin-A4-phosphate (CA4P, 10 mg/kg) significantly prolonged median survival to 35 days (range 26-42), compared to vehicle control (20 days, range 16-29), CA4P alone (22 days, range 18-30), and \(^{131}\)I-prohypericin alone (27 days, range 20-33). The combination therapy significantly inhibited tumor growth and extended tumor doubling time (16.1 ± 0.7 days) compared to vehicle control (7.8 ± 0.9 days), CA4P alone (7.3 ± 0.3 days), and \(^{131}\)I-prohypericin alone (8.0 ± 1.7 days). [2]
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| Animal Protocol |
For biodistribution analysis, A549 tumor-bearing nude mice were intravenously injected with \(^{131}\)I-prohypericin (18.5 MBq/Kg) alone, or received sequential intravenous injections of CA4P (10 mg/kg) followed 24 h later by \(^{131}\)I-prohypericin (18.5 MBq/Kg). Animals were sacrificed at 4 h, 24 h, and 120 h post-injection (n=6 per time point). Tissues were harvested, weighed, and radioactivity was measured using an automatic gamma counter. [2]
For the tumor necrosis targeted radiotherapy study, tumor-bearing nude mice were divided into four groups (n=9 per group). Group A received vehicle controls. Group B received CA4P (10 mg/kg) and solvent of \(^{131}\)I-prohypericin. Group C received \(^{131}\)I-prohypericin (185 MBq/Kg) and solvent of CA4P. Group D received sequential intravenous injections of CA4P (10 mg/kg) and \(^{131}\)I-prohypericin (185 MBq/Kg) 24 h after CA4P. Body weight was recorded daily. Blood was collected at day 20 (n=3 per group) for hematological and biochemical analysis. Time to endpoint was recorded for survival analysis. [2] For anatomical autoradiography, animals in Group D were sacrificed at day 5, 10, and 20 post-administration (n=2 per time point), frozen, and cut into 0.5 cm slices for exposure to a storage phosphor screen. [2] |
| ADME/Pharmacokinetics |
The plasma elimination half-life of protohypericin was 14.9 hours in a rat model of reperfused hepatic infarction (based on a previous study cited within the paper). [2]
In A549 tumor-bearing nude mice, the highest radioactivity retention of \(^{131}\)I-prohypericin in most normal tissues occurred at the early time point (4 h) after administration and decreased rapidly thereafter up to 120 h, except in necrotic tumor. High uptakes of \(^{131}\)I-prohypericin were found in the liver, viable tumor, and necrotic tumor through all time points. The radioactivity accumulation of \(^{131}\)I-prohypericin in the necrotic tumor of the CA4P + \(^{131}\)I-prohypericin group was significantly higher than that of the \(^{131}\)I-prohypericin alone group at 4 h, 24 h, and 120 h (p< 0.05). The necrosis-to-viable tumor ratios from gamma counting were 0.9, 2.3, 2.8 in the \(^{131}\)I-prohypericin alone group, and 1.0, 2.6, 5.3 in the CA4P + \(^{131}\)I-prohypericin group at 4 h, 24 h, and 120 h, respectively. [2] |
| Toxicity/Toxicokinetics |
In tumor-bearing nude mice, treatment with \(^{131}\)I-prohypericin alone or in combination with CA4P displayed no obvious inhibitory effect on the blood system or immune system. White blood cell numbers in treatment groups (Group C and D) were significantly higher than the vehicle control group (Group A), which might be caused by the therapeutic response. No significant differences were observed in red blood cells, platelets, or hemoglobin levels between groups. [2]
Hepatic function indexes (ALT, AST, ALB) and renal function indexes (BUN, CREA, UA) showed no obvious difference between the \(^{131}\)I-prohypericin treatment groups (Group C and D) and the vehicle control group (Group A), suggesting no signs of liver or kidney tissue damage after treatment. [2] |
| References |
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| Additional Infomation |
Prohyperin is a phenanthrene alcohol compound. It has been reported that prohyperin has been found in Polygala tenuifolia, St. John's wort, and Mycorrhiza rubrum, and relevant data are available for reference.
Protohypericin is used as a necrosis-avid agent for tumor necrosis targeted radiotherapy (TNTR). The compound can be radiolabeled with \(^{131}\)I. The combination of \(^{131}\)I-prohypericin with the vascular disrupting agent CA4P provides a synergistic effect by inducing massive tumor necrosis (via CA4P) and then delivering radiotherapy to the necrotic regions (via \(^{131}\)I-prohypericin). This strategy is proposed for the treatment of solid tumors, including non-small cell lung cancer (NSCLC). The mechanism for the necrosis affinity of prohypericin remains unclear. [2] |
| Molecular Formula |
C30H18O8
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|---|---|
| Molecular Weight |
506.4591
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| Exact Mass |
476.126
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| CAS # |
548-03-8
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| PubChem CID |
164660
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| Appearance |
Purple to black solid
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| Density |
1.736g/cm3
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| Boiling Point |
954.3ºC at 760mmHg
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| Flash Point |
544.7ºC
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| LogP |
6.894
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
0
|
| Heavy Atom Count |
38
|
| Complexity |
1270
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O([H])C1=C2C(C([H])=C(C([H])([H])[H])C([H])=C2C2C3C1=C(C([H])=C(C=3C1C(=C([H])C(=C3C(=C4C(C([H])=C(C([H])([H])[H])C([H])=C4C=2C=13)=O)O[H])O[H])O[H])O[H])O[H])=O
|
| InChi Key |
DPKVSJZTYNGFAW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H18O8/c1-9-3-11-19(13(31)5-9)29(37)25-17(35)7-15(33)23-24-16(34)8-18(36)26-28(24)22(21(11)27(23)25)12-4-10(2)6-14(32)20(12)30(26)38/h3-8,33-38H,1-2H3
|
| Chemical Name |
9,11,13,16,18,20-hexahydroxy-5,24-dimethylheptacyclo[13.11.1.12,10.03,8.019,27.021,26.014,28]octacosa-1,3,5,8,10,12,14(28),15(27),16,18,20,23,25-tridecaene-7,22-dione
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~246.81 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.11 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9745 mL | 9.8724 mL | 19.7449 mL | |
| 5 mM | 0.3949 mL | 1.9745 mL | 3.9490 mL | |
| 10 mM | 0.1974 mL | 0.9872 mL | 1.9745 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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