Abstract
Precision medicine in the form of molecularly-targeted therapies are now the frontline in the treatment of cancer, buoyed by tangible improvements in treatment tolerability and outcomes (Teicher in Mol Cancer Ther, pp. 7–40, 2005 [1]). Nonetheless, drug resistance against targeted therapies almost inevitably arises eventually after several treatment cycles.
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Supplementary Scheme
Synthesis of platinum(IV)-AHNP conjugates. Reaction conditions: (I) succinimidyl 4-formylbenzoate, in DMSO, r.t. (II) acetic anhydride in DMF, r.t. (III) H2O2 in acetic acid, r.t. (IV) 4-formyl-benzoyl chloride in acetone, pyridine, reflux. AHNP: H2N-YC*DGFYAC*YMDVGGKK(aminooxy)-CONH2; dAHNP: fC*DGFYAC*yMDVGGKK(aminooxy)-CONH2 (*—Linked disulfide bridge)
Supplementary Table
Measurements of cellular ROS on NCI-N87 after drug-treatment using 2′,7′–dichlorofluorescein diacetate (DCFDA) which measures general oxidative stress. In some cases, cells were co-treated with butylated hydroxyanisole (BHA), an antioxidant. t-butyl hydroperoxide-treated cells was included as a positive control
Intermediate-term potency of the drug conjugates as determined by MTT measurements of cellular metabolic activity after 72 h drug treatment against the NCI-N87 gastric cancer cell line. a Representative dosage-response curves. b Table of absolute IC50 (µM). Platinum concentrations were calibrated by ICP-OES
Visual flouresence microscopy monitoring of drug-treated NCI-N87 over time. NCI-N87 was drug-treated (15 μM for 24 h and then allowed to recover in fresh media). Nuclear morphology were visualized by Hoechst 3342 staining. There were substantial floating dead cells in drug-treated cells in the initial 24 h drug-treatment period (not shown here). When allowed to recover after 24 h drug-treatment, 4a-treated cells undergoes a transient phase of cell-profileration, as evidenced by a decrease in empty space at 144 h. The cells exhibited increasingly abnormal nuclear morphology over time, implying that continued long-term profileration was unviable
Cell-cycle distribution of drug-treated NCI-N87 cells over time. Drug-treated cells were permeabilized with 70% v/v ethanol and stained with propodium iodide to determine DNA content
Representative photos of clonogenic assay on NCI-N87 to assess the long-term proliferation ability of drug-treated cells. Single cells were seeded in a 6-well plate, drug-treated for 24 h and allowed to recover in fresh complete media for a further 15 d before counting the number of colonies formed. The number of single cells seeded per well is written on the plates
Characterisation of Compounds
See Figs. S4.6a, b, c, 4.7a, b, S4.8a, b, S4.9a, b, S4.10a, b.
a 1H NMR of oxaliplatin(IV)-benzaldehyde scaffold 2 in DMSO-d6. b ESI-MS (−) characterisation of 2: Fullscan, zoom scan (isotopic pattern) and MS/MS (top to bottom). m/z: Calculated 604.5 [M−H]−, found 604.0. c RP-HPLC purity assessment of 2 dissolved in MeCN-H2O using Shimpack VP-ODS column (150 × 5.60 mm i.d). Elution condition: 8–30% solvent B for 10 min, 30% solvent B for 8 min and finally 30–80% solvent B for 7 min
a ESI-MS (−) characterisation of cisplatin(IV)-AHNP conjugate 3a: Fullscan and zoom scan (isotopic pattern) m/z: calculated 1189.1 [M−2H]2−, found 1188.6. b HPLC chromatogram of cisplatin(IV)-AHNP conjugate 3a. The purity of the compound was assessed using Shimpack VP-ODS column (150 × 5.60 mm i.d). Elution Condition: 8–30% solvent B for 10 min, 30% solvent B for 8 min and finally 30–80% solvent B for 7 min
a ESI-MS (−) characterisation of cisplatin(IV)-dAHNP conjugate 3b: Fullscan and zoom scan (isotopic pattern) m/z: calculated 1181.1 [M−2H]2−, found 1180.9. b HPLC chromatogram of cisplatin(IV)-dAHNP conjugate 3b. The purity of the compound was assessed using Shimpack VP-ODS column (150 × 5.60 mm i.d). Elution Condition: 8–30% solvent B for 10 min, 30% solvent B for 8 min and finally 30–80% solvent B for 7 min
a ESI-MS (−) characterisation of oxaliplatin(IV)-AHNP conjugate 4a: Fullscan and zoom scan (isotopic pattern) m/z: calculated 1237.8 [M−2H]2−, found 1237.1. b HPLC chromatogram of oxaliplatin(IV)-AHNP conjugate 4a. The purity of the compound was assessed using Shimpack VP-ODS column (150 × 5.60 mm i.d). Elution Condition: 8–30% solvent B for 10 min, 30% solvent B for 8 min and finally 30–80% solvent B for 7 min
a ESI-MS (−) characterisation of oxaliplatin(IV)-dAHNP conjugate 4b: Fullscan and zoom scan (isotopic pattern) m/z: calculated 1229.8 [M−2H]2−, found 1229.6. b HPLC chromatogram of oxaliplatin(IV)-dAHNP conjugate 4b. The purity of the compound was assessed using Shimpack VP-ODS column (150 × 5.60 mm i.d). Elution Condition: 8–30% solvent B for 10 min, 30% solvent B for 8 min and finally 30–80% solvent B for 7 min
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Wong, D.Y.Q. (2018). Induction of Targeted Necrosis with HER2-Targeted Platinum(IV) Anticancer Prodrugs. In: Rethinking Platinum Anticancer Drug Design: Towards Targeted and Immuno-chemotherapeutic Approaches. Springer Theses. Springer, Singapore. https://doi.org/10.1007/978-981-10-8594-9_4
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