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| Targets |
DNA synthesis; active intermediate of Gemcitabine
Deoxycytidine analog; Gemcitabine monophosphate is a nucleotide analog that acts as a key metabolite of gemcitabine. It is incorporated into DNA during replication, leading to chain termination and apoptosis. It inhibits ribonucleotide reductase, further depleting the deoxynucleotide pool. It targets DNA synthesis in rapidly dividing cancer cells. |
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| ln Vitro |
There is an urgent need for new therapeutics for the treatment of aggressive and metastatic refractory human non-small-cell lung cancer (NSCLC). Antiangiogenesis therapy and chemotherapy are the two major treatment options. Unfortunately, both types of therapies when used individually have their disadvantages. Integrating antiangiogenesis therapy with chemotherapy is expected to target the tumor's vascular endothelial cells and the tumor cells simultaneously. In this study, we coformulated Vascular endothelial growth factor (VEGF) siRNA targeting VEGFs and gemcitabine monophosphate (GMP) into a single cell-specific, targeted lipid/calcium/phosphate (LCP) nanoparticle formulation.[1]
Combination chemotherapy is a common practice in clinical management of malignancy. Synergistic therapeutic outcome is only achieved when tumor cells are exposed to cells in an optimal ratio. However, due to diverse physicochemical properties of drugs, no free drug cocktails or nanomaterials are capable of co-loading and co-delivering drugs at an optimal ratio. Herein, we develop a novel nano-platform with precise ratiometric co-loading and co-delivery of two hydrophilic drugs for synergistic anti-tumor effects. Based on previous work, we utilize a solvent displacement method to ratiometrically load dioleoyl phosphatidic acid (DOPA)-gemcitabine monophosphate and DOPA coated cisplatin-precipitate nanocores into the same PLGA NP. These cores are designed to have similar hydrophobic surface properties. GMP and cisplatin are engineered into PLGA NP at an optimal synergistic ratio (5:1, mol:mol) with over 70% encapsulation efficiency and were ratiometrically taken up by tumor cells in vitro and in vivo[2]. In vitro, gemcitabine monophosphate shows synergistic anti-cancer effects when used in nanoparticle form in combination with cisplatin nanoparticles at a one-to-one molar ratio, with IC50s of 5.95 and 34.8 for specific assays. It is the active intracellular form of the prodrug gemcitabine that exerts its cytotoxic effects. |
| ln Vivo |
Antitumor effect of the combination therapy using LCP loaded with both VEGF siRNA and GMP was evaluated in both subcutaneous and orthotopic xenograft models of NSCLC with systemic administration. The improved therapeutic response, as compared with either VEGF siRNA or GMP therapy alone, was supported by the observation of 30-40% induction of tumor cell apoptosis, eightfold reduction of tumor cell proliferation and significant decrease of tumor microvessel density (MVD). The combination therapy led to dramatic inhibition of tumor growth, with little in vivo toxicity. In addition, the current studies demonstrated the possibility of incorporating multiple nucleic acid molecules and phosphorylated small-molecule drugs, targeting to different pathways, into a single nanoparticle formulation for profound therapeutic effect.[1]
These PLGA NP exhibit synergistic anti-cancer effects in a stroma-rich bladder tumor model. A single injection of dual drugs in PLGA NP can significantly inhibit tumor growth. This nanomaterial-system solves problems related to ratiometric co-loading and co-delivery of different hydrophilic moieties and provides possibilities for co-loading hydrophilic drugs with hydrophobic drugs for combination therapy[2]. Specific in vivo activity data for gemcitabine monophosphate are not extensively documented. However, as the active metabolite of gemcitabine, it is responsible for the in vivo antitumor activity observed with gemcitabine treatment. Gemcitabine is widely used in the clinic for various cancers. |
| Enzyme Assay |
In vitro, synergistic effects are evaluated by combining gemcitabine monophosphate with cisplatin in nanoparticle form at a one-to-one molar ratio. Cancer cells are treated with the combination, and cell viability is measured using standard assays to determine IC50 values.
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| Cell Assay |
Cell lines are treated with gemcitabine monophosphate alone or in combination with other agents. The compound is typically dissolved in DMSO or water. Cell viability is assessed after a defined exposure period (e.g., 72 hours) using assays such as MTT or CellTiter-Glo.
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| Animal Protocol |
In vivo protocols are based on the parent drug gemcitabine. Gemcitabine is administered intravenously to tumor-bearing mice. Efficacy is evaluated by measuring tumor growth inhibition. Gemcitabine monophosphate is the active intracellular metabolite responsible for the observed antitumor activity.
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| ADME/Pharmacokinetics |
Gemcitabine monophosphate has a molecular weight of 343.18 and formula C9H12F2N3O7P. It is a crystalline solid. It is soluble in DMF, DMSO, and PBS at 10 mg/ml. It has a UV absorbance maximum at 271 nm. Storage: -20°C.
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| Toxicity/Toxicokinetics |
Specific toxicity data are not extensively documented. As a metabolite of gemcitabine, its toxicity profile is expected to be similar, including myelosuppression. The compound is for research use only.
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| References |
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| Additional Infomation |
See also: Gemcitabine 5'-monophosphate (note moved to).
Gemcitabine monophosphate is also known as Gemcitabine 5'-phosphate. It is a nucleotide analog and a key intermediate in the activation pathway of gemcitabine. It is used in research to study the pharmacology of gemcitabine and in analytical method development. |
| Molecular Formula |
C9H12N3O7F2P.CH2O2
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|---|---|
| Molecular Weight |
389.20346
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| Exact Mass |
343.038
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| CAS # |
116371-67-6
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| PubChem CID |
503015
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| Appearance |
Typically exists as White to off-white solids at room temperature
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| Density |
2.09
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| Boiling Point |
618.3ºC at 760 mmHg
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| Melting Point |
151-153 °C
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| Flash Point |
327.736ºC
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| Index of Refraction |
1.681
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| LogP |
-3
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
22
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| Complexity |
578
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| Defined Atom Stereocenter Count |
3
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| SMILES |
OC=O.OP(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)[C@@H]1O)(O)=O
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| InChi Key |
KNTREFQOVSMROS-QPPQHZFASA-N
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| InChi Code |
InChI=1S/C9H12F2N3O7P/c10-9(11)6(15)4(3-20-22(17,18)19)21-7(9)14-2-1-5(12)13-8(14)16/h1-2,4,6-7,15H,3H2,(H2,12,13,16)(H2,17,18,19)/t4-,6-,7-/m1/s1
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| Chemical Name |
[(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-3-hydroxyoxolan-2-yl]methyl dihydrogen phosphate
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| Synonyms |
5'-Cytidylic acid, 2'-deoxy-2',2'-difluoro-; [(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-3-hydroxyoxolan-2-yl]methyl dihydrogen phosphate; dFdCMP; ((2R,3R,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl dihydrogen phosphate; Gemcitabinemonophosphate; 2',2'-difluorodeoxycytidine monophosphate;
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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: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~200 mg/mL (~582.78 mM)
H2O : ~100 mg/mL (~291.39 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (14.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 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. Solubility in Formulation 2: ≥ 5 mg/mL (14.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 5 mg/mL (14.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5694 mL | 12.8469 mL | 25.6937 mL | |
| 5 mM | 0.5139 mL | 2.5694 mL | 5.1387 mL | |
| 10 mM | 0.2569 mL | 1.2847 mL | 2.5694 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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