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Immuno-Chemotherapeutic Platinum(IV) Prodrugs of Cisplatin as Multimodal Anticancer Agents

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Rethinking Platinum Anticancer Drug Design: Towards Targeted and Immuno-chemotherapeutic Approaches

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Abstract

For the longest time, the contribution of the immune system in chemotherapy has been disregarded as cytotoxic drugs are generally believed to be immunosuppressive [1,2,3,4,5]. Consequently, evaluation of new chemotherapeutic agents involved screening of drug candidates upon xenografted tumors in immunodeficient mice which neglects any possible immune contribution.

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References

  1. Lake, R.A., Robinson, B.W.S.: Immunotherapy and chemotherapy—a practical partnership. Nat. Rev. Cancer 5, 397–405 (2005)

    Article  CAS  PubMed  Google Scholar 

  2. Zitvogel, L., Apetoh, L., Ghiringhelli, F., Kroemer, G.: Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008)

    Article  CAS  PubMed  Google Scholar 

  3. Lesterhuis, W.J., Haanen, J.B.A.G., Punt, C.J.A.: Cancer immunotherapy—revisited. Nat. Rev. Drug Discov. 10, 591–600 (2011)

    Article  CAS  PubMed  Google Scholar 

  4. Galluzzi, L., Senovilla, L., Zitvogel, L., Kroemer, G.: The secret ally: immunostimulation by anticancer drugs. Nat. Rev. Drug Discov. 11, 215–233 (2012)

    Article  CAS  PubMed  Google Scholar 

  5. Krysko, D.V., Garg, A.D., Kaczmarek, A., Krysko, O., Agostinis, P., Vandenabeele, P.: Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860–875 (2012)

    Article  CAS  PubMed  Google Scholar 

  6. Hall, M.D., Mellor, H.R., Callaghan, R., Hambley, T.W.: Basis for design and development of Platinum(IV) anticancer complexes. J. Med. Chem. 50, 3403–3411 (2007)

    Article  CAS  PubMed  Google Scholar 

  7. Hall, M.D., Hambley, T.W.: Platinum(IV) antitumour compounds: their bioinorganic chemistry. Coord. Chem. Rev. 232, 49–67 (2002)

    Article  CAS  Google Scholar 

  8. Chin, C.F., Wong, D.Y.Q., Jothibasu, R., Ang, W.H.: Anticancer Platinum(IV) prodrugs with novel modes of activity. Curr. Top. Med. Chem. 11, 2602–2612 (2011)

    Article  CAS  PubMed  Google Scholar 

  9. Kelland, L.: The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 7, 573–584 (2007)

    Article  CAS  PubMed  Google Scholar 

  10. Abu-Surrah, A.S., Kettunen, M.: Platinum group antitumor chemistry: design and development of new anticancer drugs complementary to cisplatin. Curr. Med. Chem. 13, 1337–1357

    Article  CAS  PubMed  Google Scholar 

  11. Wang, D., Lippard, S.J.: Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discov. 4, 307–320 (2005)

    Article  CAS  PubMed  Google Scholar 

  12. Reed, E.: Cisplatin, carboplatin, and oxaliplatin. In: Chabner, B.A., Longo, D.L. (eds.) Cancer chemotherapy and biotherapy: principles and practice, 5th edn, pp. 333–341. Lippincott Williams & Wilkins, Philadelphia (2011)

    Google Scholar 

  13. Tesniere, A., Schlemmer, F., Boige, V., Kepp, O., Martins, I., Ghiringhelli, F., Aymeric, L., Michaud, M., Apetoh, L., Barault, L., Mendiboure, J., Pignon, J.P., Jooste, V., van Endert, P., Ducreux, M., Zitvogel, L., Piard, F., Kroemer, G.: Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2009)

    Article  CAS  PubMed  Google Scholar 

  14. Merritt, R.E., Mahtabifard, A., Yamada, R.E., Crystal, R.G., Korst, R.J.: Cisplatin augments cytotoxic T-lymphocyte-mediated antitumor immunity in poorly immunogenic murine lung cancer. J. Thorac. Cardiovasc. Surg. 126, 1609–1617 (2003)

    Article  CAS  PubMed  Google Scholar 

  15. Ramakrishnan, R., Assudani, D., Nagaraj, S., Hunter, T., Cho, H.-I., Antonia, S., Altiok, S., Celis, E., Gabrilovich, D.I.: Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J. Clin. Invest. 120, 1111–1124 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lesterhuis, W.J., Punt, C.J.A., Hato, S.V., Eleveld-Trancikova, D., Jansen, B.J.H., Nierkens, S., Schreibelt, G., de Boer, A., Van Herpen, C.M.L., Kaanders, J.H., van Krieken, J.H.J.M., Adema, G.J., Figdor, C.G., de Vries, I.J.M.: Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J. Clin. Investig. 121, 3100–3108 (2011)

    Article  CAS  PubMed  Google Scholar 

  17. Kleinerman, E.S., Zwelling, L.A., Muchmore, A.V.: Enhancement of naturally occurring human spontaneous monocyte-mediated cytotoxicity by cis-Diamminedichloroplatinum(II). Cancer Res. 40, 3099–3102 (1980)

    PubMed  CAS  Google Scholar 

  18. Kleinerman, E., Howser, D., Young, R., Bull, J., Zwelling, L., Barlock, A., Decker, J., Muchmore, A.: Defective monocyte killing in patients with malignancies and restoration of function during chemotherapy. Lancet 316, 1102–1105 (1980)

    Article  Google Scholar 

  19. Lichtenstein, A.K., Pende, D.: Enhancement of natural killer cytotoxicity by cis-Diamminedichloroplatinum(II) in vivo and in vitro. Cancer Res. 46, 639–644 (1986)

    PubMed  CAS  Google Scholar 

  20. Son, K., Kim, Y.-M.: In vivo cisplatin-exposed macrophages increase immunostimulant-induced nitric oxide synthesis for tumor cell killing. Cancer Res. 55, 5524–5527 (1995)

    PubMed  CAS  Google Scholar 

  21. Okamoto, M., Kasetani, H., Kaji, R., Goda, H., Ohe, G., Yoshida, H., Sato, M., Kasatani, H.: cis-Diamminedichloroplatinum and 5-fluorouracil are potent inducers of the cytokines and natural killer cell activity in vivo and in vitro. Cancer Immunol. Immunother. 47, 233–241 (1998)

    Article  CAS  PubMed  Google Scholar 

  22. Singh, R.A.K., Sodhi, A.: Antigen presentation by cisplatin-activated macrophages: role of soluble factor(s) and second messengers. Immunol. Cell Biol. 76, 513–519 (1998)

    Article  CAS  PubMed  Google Scholar 

  23. Hu, J., Kinn, J., Zirakzadeh, A.A., Sherif, A., Norstedt, G., Wikström, A.C., Winqvist, O.: The effects of chemotherapeutic drugs on human monocyte-derived dendritic cell differentiation and antigen presentation. Clin. Exp. Immunol. 172, 490–499 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chang, C.-L., Hsu, Y.-T., Wu, C.-C., Lai, Y.-Z., Wang, C., Yang, Y.-C., Wu, T.-C., Hung, C.-F.: Dose-dense chemotherapy improves mechanisms of antitumor immune response. Cancer Res. 73, 119–127 (2013)

    Article  CAS  PubMed  Google Scholar 

  25. Rosenberg, B.: Possible mechanisms for the antitumor activity of platinum coordination complexes. Cancer Chemother. Rep. 59, 589–598 (1975)

    PubMed  Google Scholar 

  26. Taniguchi, K., Nishiura, H., Yamamoto, T.: Requirement of the acquired immune system in successful cancer chemotherapy with cis-Diamminedichloroplatinum(II) in a syngeneic mouse tumor transplantation model. J. Immunother. 34, 480–489 (2011)

    Article  CAS  PubMed  Google Scholar 

  27. Wong, D.Y.Q., Lau, J.Y., Ang, W.H.: Harnessing chemoselective imine ligation for tethering bioactive molecules to platinum(iv) prodrugs. Dalton Trans. 41, 6104–6111 (2012)

    Article  CAS  PubMed  Google Scholar 

  28. Khau, T., Langenbach, S.Y., Schuliga, M., Harris, T., Johnstone, C.N., Anderson, R.L., Stewart, A.G.: Annexin-1 signals mitogen-stimulated breast tumor cell proliferation by activation of the formyl peptide receptors (FPRs) 1 and 2. FASEB J 25, 483–496 (2011)

    Article  CAS  PubMed  Google Scholar 

  29. Coffelt, S.B., Tomchuck, S.L., Zwezdaryk, K.J., Danka, E.S., Scandurro, A.B.: Leucine Leucine-37 uses formyl peptide receptor-like 1 to activate signal transduction pathways, stimulate oncogenic gene expression, and enhance the invasiveness of ovarian cancer cells. Mol. Cancer Res. 7, 907–915 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang, J., Chen, K., Chen, J., Gong, W., Dunlop, N.M., Howard, O.M.Z., Gao, Y., Bian, X.W., Wang, J.M.: The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells. Br. J. Cancer 102, 1052–1060 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhou, Y., Bian, X., Le, Y., Gong, W., Hu, J., Zhang, X., Wang, L., Iribarren, P., Salcedo, R., Howard, O.M.Z., Farrar, W., Wang, J.M.: Formylpeptide receptor FPR and the rapid growth of malignant human gliomas. J. Natl. Cancer Inst. 97, 823–835 (2005)

    Article  CAS  PubMed  Google Scholar 

  32. Kim, S.D., Lee, H.Y., Shim, J.W., Kim, H.J., Baek, S.-H., Zabel, B.A., Bae, Y.-S.: A WKYMVm-containing combination elicits potent anti-tumor activity in heterotopic cancer animal model. PLoS ONE 7, e30522 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim, S.D., Kim, J.M., Jo, S.H., Lee, H.Y., Lee, S.Y., Shim, J.W., Seo, S.-K., Yun, J., Bae, Y.-S.: Functional expression of formyl peptide receptor family in human NK cells. J. Immunol. 183, 5511–5517 (2009)

    Article  CAS  PubMed  Google Scholar 

  34. Le, Y., Yang, Y., Cui, Y., Yazawa, H., Gong, W., Qiu, C., Wang, J.M.: Receptors for chemotactic formyl peptides as pharmacological targets. Int. Immunopharmacol. 2, 1–13 (2002)

    Article  CAS  PubMed  Google Scholar 

  35. Tsubery, H., Yaakov, H., Cohen, S., Giterman, T., Matityahou, A., Fridkin, M., Ofek, I.: Neopeptide antibiotics that function as opsonins and membrane-permeabilizing agents for gram-negative bacteria. Antimicrob. Agents Chemother. 49, 3122–3128 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wan, L., Zhang, X., Pooyan, S., Palombo, M.S., Leibowitz, M.J., Stein, S., Sinko, P.J.: Optimizing size and copy number For PEG-fMLF (N-Formyl-methionyl-leucyl-phenylalanine) nanocarrier uptake by macrophages. Bioconjug. Chem. 19, 28–38 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Niedel, J.E., Kahane, I., Cuatrecasas, P.: Receptor-mediated internalization of fluorescent chemotactic peptide by human neutrophils. Science 205, 1412–1414 (1979)

    Article  CAS  PubMed  Google Scholar 

  38. Lee, C.G., Choi, S.Y., Park, S.-H., Park, K.S., Ryu, S.H., Sung, Y.C.: The synthetic peptide Trp-Lys-Tyr-Met-Val-d-Met as a novel adjuvant for DNA vaccine. Vaccine 23, 4703–4710 (2005)

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, J.Z., Bonnitcha, P., Wexselblatt, E., Klein, A.V., Najajreh, Y., Gibson, D., Hambley, T.W.: Facile preparation of mono-, di- and mixed-Carboxylato Platinum(IV) complexes for versatile anticancer prodrug design. Chem. Eur. J. 19, 1672–1676 (2013)

    Article  CAS  PubMed  Google Scholar 

  40. Perretti, M.: The annexin 1 receptor(s): is the plot unravelling? Trends Pharmacol. Sci. 24, 574–579 (2003)

    Article  CAS  PubMed  Google Scholar 

  41. Le, Y., Murphy, P.M., Wang, J.M.: Formyl-peptide receptors revisited. Trends Immunol. 23, 541–548 (2002)

    Article  CAS  PubMed  Google Scholar 

  42. Alborzinia, H., Can, S., Holenya, P., Scholl, C., Lederer, E., Kitanovic, I., Wölfl, S.: Real-time monitoring of cisplatin-induced cell death. PLoS ONE 6, e19714 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pooyan, S., Qiu, B., Chan, M.M., Fong, D., Sinko, P.J., Leibowitz, M.J., Stein, S.: Conjugates bearing multiple formyl-methionyl peptides display enhanced binding to but not activation of phagocytic cells. Bioconjug. Chem. 13, 216–223 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Graf, N., Mokhtari, T.E., Papayannopoulos, I.A., Lippard, S.J.: Platinum(IV)-chlorotoxin (CTX) conjugates for targeting cancer cells. J. Inorg. Biochem. 110, 58–63 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mukhopadhyay, S., Barnés, C.M., Haskel, A., Short, S.M., Barnes, K.R., Lippard, S.J.: Conjugated Platinum(IV)–Peptide complexes for targeting angiogenic tumor vasculature. Bioconjug. Chem. 19, 39–49 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gaviglio, L., Gross, A., Metzler-Nolte, N., Ravera, M.: Synthesis and in vitro cytotoxicity of cis,cis,trans-diamminedichloridodisuccinatoplatinum(iv)-peptide bioconjugates. Metallomics 4, 260–266 (2012)

    Article  CAS  PubMed  Google Scholar 

  47. Abramkin, S., Valiahdi, S.M., Jakupec, M.A., Galanski, M., Metzler-Nolte, N., Keppler, B.K.: Solid-phase synthesis of oxaliplatin-TAT peptide bioconjugates. Dalton Trans. 41, 3001–3005 (2012)

    Article  CAS  PubMed  Google Scholar 

  48. Chin, C.F., Tian, Q., Setyawati, M.I., Fang, W., Tan, E.S.Q., Leong, D.T., Ang, W.H.: Tuning the activity of Platinum(IV) anticancer complexes through asymmetric acylation. J. Med. Chem. 55, 7571–7582 (2012)

    Article  CAS  PubMed  Google Scholar 

  49. Ang, W.H., Pilet, S., Scopelliti, R., Bussy, F., Juillerat-Jeanneret, L., Dyson, P.J.: Synthesis and characterization of Platinum(IV) anticancer drugs with functionalized aromatic carboxylate ligands: influence of the ligands on drug efficacies and uptake. J. Med. Chem. 48, 8060–8069 (2005)

    Article  CAS  PubMed  Google Scholar 

  50. Varbanov, H., Valiahdi, S.M., Legin, A.A., Jakupec, M.A., Roller, A., Galanski, M., Keppler, B.K.: Synthesis and characterization of novel bis(carboxylato)dichloridobis(ethylamine)platinum(IV) complexes with higher cytotoxicity than cisplatin. Eur. J. Med. Chem. 46, 5456–5464 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gunaseelan, S., Gunaseelan, K., Deshmukh, M., Zhang, X., Sinko, P.J.: Surface modifications of nanocarriers for effective intracellular delivery of anti-HIV drugs. Adv. Drug Deliv. Rev. 62, 518–531 (2010)

    Article  CAS  PubMed  Google Scholar 

  52. Qin, Y., Li, Z.-W., Yang, Y., Yu, C.-M., Gu, D.-D., Deng, H., Zhang, T., Wang, X., Wang, A.-P., Luo, W.-Z.: Liposomes formulated with fMLP-modified cholesterol for enhancing drug concentration at inflammatory sites. J. Drug Target. 22, 165–174 (2014)

    Article  CAS  PubMed  Google Scholar 

  53. Banerjee, G., Medda, S., Basu, M.K.: A novel peptide-grafted liposomal delivery system targeted to macrophages. Antimicrob. Agents Chemother. 42, 348–351 (1998)

    PubMed  PubMed Central  CAS  Google Scholar 

  54. van de Loosdrecht, A.A., Nennie, E., Ossenkoppele, G.J., Beelen, R.H.J., Langenhuijsen, M.M.A.C.: Cell mediated cytotoxicity against U 937 cells by human monocytes and macrophages in a modified colorimetric MTT assay: a methodological study. J. Immunol. Methods 141, 15–22 (1991)

    Article  PubMed  Google Scholar 

  55. Sodhi, A., Pai, K., Singh, R.K., Singh, S.M.: Activation of human NK cells and monocytes with cisplatin in vitro. Int. J. Immunopharmacol. 12, 893–898 (1990)

    Article  CAS  PubMed  Google Scholar 

  56. Sodhi, A., Pai, K.: Increased production of interleukin-1 and tumor necrosis factor by human monocytes treated in vitro with cisplatin or other biological response modifiers. Immunol. Lett. 34, 183–188 (1992)

    Article  CAS  PubMed  Google Scholar 

  57. Sodhi, A., Chauhan, P.: Interaction between cisplatin treated murine peritoneal macrophages and L929 cells: involvement of adhesion molecules, cytoskeletons, upregulation of Ca2+ and nitric oxide dependent cytotoxicity. Mol. Immunol. 44, 2265–2276 (2007)

    Article  CAS  PubMed  Google Scholar 

  58. Griffith, T.S., Wiley, S.R., Kubin, M.Z., Sedger, L.M., Maliszewski, C.R., Fanger, N.A.: Monocyte-mediated tumoricidal activity via the tumor necrosis factor–related cytokine. TRAIL. J. Exp. Med. 189, 1343–1354 (1999)

    Article  CAS  PubMed  Google Scholar 

  59. Chauhan, P., Sodhi, A., Tarang, S.: Cisplatin-treated murine peritoneal macrophages induce apoptosis in L929 cells: role of Fas-Fas ligand and tumor necrosis factor–tumor necrosis factor receptor 1. Anticancer Drugs 18, 187–196 (2007)

    Article  CAS  PubMed  Google Scholar 

  60. Galanski, M., Jakupec, M.A., Keppler, B.K.: Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr. Med. Chem. 12, 2075–2094 (2005)

    Article  CAS  PubMed  Google Scholar 

  61. Dhara, S.C.: A rapid method for the synthesis of cis-[Pt(NH3)2Cl2]. Indian J. Chem. 8, 193–194 (1970)

    Google Scholar 

  62. Kuroda, R., Ismail, I.M., Sadler, P.J.: X-ray and NMR studies of trans-dihydroxo-platinum(IV) antitumor complexes. J. Inorg. Biochem. 22, 103–117 (1984)

    Article  CAS  PubMed  Google Scholar 

  63. Phillips, J.A., Morgan, E.L., Dong, Y., Cole, G.T., McMahan, C., Hung, C.-Y., Sanderson, S.D.: Single-step conjugation of bioactive peptides to proteins via a self-contained succinimidyl Bis-Arylhydrazone. Bioconjug. Chem. 20, 1950–1957 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fulmer, G.R., Miller, A.J.M., Sherden, N.H., Gottlieb, H.E., Nudelman, A., Stoltz, B.M., Bercaw, J.E., Goldberg, K.I.: NMR chemical shifts of trace impurities: common laboratory solvents, organics, and gases in deuterated solvents relevant to the organometallic chemist. Organometallics 29, 2176–2179 (2010)

    Article  CAS  Google Scholar 

  65. Gill, S.C., von Hippel, P.H.: Calculation of protein extinction coefficients from amino acid sequence data. Anal. Biochem. 182, 319–326 (1989)

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Daniel Yuan Qiang Wong

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  1. Daniel Yuan Qiang Wong
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Correspondence to Daniel Yuan Qiang Wong .

Supplementary Information

Supplementary Information

Supplementary Figures

Fig. S5.1
figure 6

Platinum uptake studies of platinum(IV)-WKYMVM conjugate 4 in FPR1/2-expressing U-87MG cells after 4 h of incubation following pre-incubation with increasing concentrations of free competitive WKYMVm. ICP-MS readings were adjusted to pmol Pt per 106 cells

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Fig. S5.2
figure 7

1H NMR spectra of complex 1 in DMSO-d6 with water suppression

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Fig. S5.3
figure 8

ESI-MS (Methanol, −ve mode) characterization of complex 1: Fullscan, MS/MS and zoomscan (top to bottom): m/z: found: 464.9 [M−H]–, calculated: 466.1

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Fig. S5.4
figure 9

1H NMR spectra of complex 2 in DMSO-d6

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Fig. S5.5
figure 10

ESI-MS (Methanol, −ve mode) characterization of complex 2: Fullscan, zoomscan and MS/MS (top to bottom): m/z: found: 506.82 [M−H]−, calculated: 508.2

Full size image
Fig. S5.6
figure 11

RP-HPLC assessment of purity of Pt–Ac-benzaldehyde 2 dissolved in MeCN–H2O. Elution conditions for both spectra (A) and (B): 20–80% gradient elution system with aq. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) over 20 min at 1.0 mL/min. Column used is: Shimpack VP-ODS column (150 × 4.60 mm i.d)

Full size image
Fig. S5.7
figure 12

HPLC spectra of crude reaction mixture of Pt(IV)-OH-aminooxy-2-12 (3a) at 295 nm. Elution conditions: 8–45% B for 30 min followed by 90% B for the next 10 min. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) at 2.0 mL/min

Full size image
Fig. S5.8
figure 13

RP-HPLC assessment of purity of Pt(IV)-OH-aminooxy-2-12 (3a) dissolved in MeCN–H2O. Elution conditions: 20–80% gradient elution system with aq. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) over 20 min at 1.0 mL/min. Column used is: Shimpack VP-ODS column (150 × 4.60 mm i.d)

Full size image
Fig. S5.9
figure 14

ESI-MS (Methanol, +ve) characterization of conjugate 3a: fullscan, zoomscan and MS/MS (top to bottom): m/z: found: 915.6 [M+2H]2+ and 1831.3 [M+H]+; calculated: 1830.7

Full size image
Fig. S5.10
figure 15

HPLC spectra of crude reaction mixture of Pt(IV)-OH-aminooxy-2-26 (3b) at 295 nm. Elution conditions: 8–45% B for 38 min, 45–80% B for 2 min followed by 90% B for the next 10 min. NH4OAc buffer (20 mM, pH 7) (solvent A) and MeCN (solvent B) at 2.0 mL/min

Full size image
Fig. S5.11
figure 16

RP-HPLC assessment of purity of Pt(IV)-OH-aminooxy-2-26 (3b) dissolved in MeCN–H2O. Elution conditions: 20–80% gradient elution system with aq. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) over 20 min at 1.0 mL/min. Column used is: Shimpack VP-ODS column (150 × 4.60 mm i.d)

Full size image
Fig. S5.12
figure 17

ESI-MS (Methanol, +ve) characterization of conjugate 3b: fullscan, zoomscan and MS/MS (top to bottom): m/z: found: 1784.2 [M+2H]2+; calculated: 3568.6

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Fig. S5.13
figure 18

HPLC spectra of crude reaction mixture of Pt(IV)-OH-aminooxy-WKYMVm (3c) at 295 nm. Elution conditions: 8–50% B for 45 min followed by 90% B for the next 15 min. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) at 2.0 mL/min

Full size image
Fig. S5.14
figure 19

RP-HPLC assessment of purity of Pt(IV)-OH-aminooxy-WKYMVm (3c) dissolved in MeCN–H2O. Elution conditions: 20–80% gradient elution system with aq. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) over 20 min at 1.0 mL/min. Column used is: Shimpack VP-ODS column (150 × 4.60 mm i.d)

Full size image
Fig. S5.15
figure 20

ESI-MS (Methanol, +ve) characterization of conjugate 3c: fullscan, zoomscan and MS/MS (top to bottom): m/z: found: 1376.9 [M+H]+; calculated: 1375.4

Full size image
Fig. S5.16
figure 21

HPLC spectra of crude reaction mixture of Pt(IV)-OH-aminooxy-fMLFK (3d) at 295 nm. Elution conditions: 8–45% B for 30 min followed by 90% B for the next 10 min. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) at 2.0 mL/min

Full size image
Fig. S5.17
figure 22

RP-HPLC assessment of purity of Pt(IV)-OH-aminooxy-fMLFK (3d) dissolved in MeCN–H2O. Elution conditions: 20–80% gradient elution system with aq. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) over 20 min at 1.0 mL/min. Column used is: Shimpack VP-ODS column (150 × 4.60 mm i.d)

Full size image
Fig. S5.18
figure 23

ESI-MS (Methanol, −ve) characterization of conjugate 3d: zoomscan, MS/MS and fullscan (top to bottom): m/z: found: 1084.1 [M−H]−; calculated: 1085.3

Full size image
Fig. S5.19
figure 24

HPLC spectra of crude reaction mixture of Pt(IV)-Ac-aminooxy-WKYMVm (4) at 295 nm. Elution conditions: 8–50% B for 45 min followed by 90% B for the next 15 min. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) at 2.0 mL/min

Full size image
Fig. S5.20
figure 25

RP-HPLC assessment of purity of Pt(IV)-Ac-aminooxy-WKYMVm (4) dissolved in MeCN–H2O. Elution conditions: 20–80% gradient elution system with aq. NH4OAc buffer (10 mM, pH 7) (solvent A) and MeCN (solvent B) over 20 min at 1.0 mL/min. Column used is: Shimpack VP-ODS column (150 × 4.60 mm i.d)

Full size image
Fig. S5.21
figure 26

ESI-MS (Methanol, +ve) characterization of conjugate 4: zoomscan, MS/MS and fullscan (top to bottom): m/z: found: 1419.1 [M−H]−; calculated: 1419.4

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Supplementary Methods

General procedure for synthesis of platinum(IV)-peptide conjugates. In general, the platinum(IV)-peptide conjugates (3a–d and 4) were prepared by treating the desired (aminooxy)acetylated peptide with 2 × stoichiometric excess of 1 or 2 in an aq. buffered solution containing 50% v/v DMSO. All reagents were pre-dissolved in DMSO to form stock solutions for addition. Concentrations of the free peptides were measured by UV at 280 nm in 50 mM pH 7 phosphate buffer. Reaction progress was followed by analytical HPLC over 24 h using a gradient elution of 5–30% B in the first 15 min followed by 30–80% B for 10 min. The desired products were subsequently isolated by semi-preparative HPLC. Purity of the conjugates was assessed using a gradient elution of 20–80% B over 20 min. Unless otherwise stated, solvent A is aq. NH4OAc buffer (10 mM, pH 7) and solvent B is MeCN.

Platinum(IV)-peptide conjugate of 1 and ANXA1(2-12) (3a). Complex 1 (50 µL of a 75.1 mM stock solution) was added to aminooxy-functionalized ANXA1 (2–12) peptide (50 µL of a 35 mM stock solution) in 1 mL 50% DMSO–NaOAc (50 mM, pH 5.5) and stirred overnight. The mono-conjugated product was subsequently purified by semi-preparative HPLC using a gradient elution system of 8–45% B for 30 min followed by 90% B for the next 10 min; ESI-MS (+): m/z 915.6 [M+2H]2+ 1831.3 [M+H]+; Purity (HPLC): 99% at 254 nm.

Platinum(IV)-peptide conjugate of 1 and ANXA1(2-26) (3b). Synthesis was similar to 3a but in 1 mL DMSO–KH2PO4 (50 mM, pH 7.5). The mono-conjugated product was subsequently purified by semi-preparative HPLC using a gradient elution system of 8–45% B for 38 min, 45–80% B for 2 min followed by 90% B for the next 10 min where solvent A is aq. NH4OAc buffer (20 mM, pH 7); ESI-MS (+): m/z 1784.2 [M+2H]2+; Purity (HPLC): 95% at 254 nm.

Platinum(IV)-peptide conjugate of 1 and WKYMVm (3c). Synthesis was as 3a. The mono-conjugated product was subsequently purified by semi-preparative HPLC using a gradient elution system of 8–50% B in the first 45 min followed by 90% B for 15 min. ESI-MS (+): m/z 1376.9 [M+H]+; Purity (HPLC): 95% at 254 nm.

Platinum(IV)-peptide conjugate of 1 and fMLFK (3d). Synthesis was as 3a. The mono-conjugated product was subsequently purified by semi-preparative HPLC using a gradient elution system of 8–45% B for 30 min followed by 90% for the next 10 min; ESI-MS (−): m/z 1084.1 [M−H]−; Purity (HPLC): 87% at 254 nm.

Platinum(IV)-peptide conjugate of 2 and WKYMVm (4). Synthesis was similar to 3c but with complex 2. ESI-MS (+): m/z 1419.1 [M+H]+; Purity (HPLC): 99% at 254 nm.

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Wong, D.Y.Q. (2018). Immuno-Chemotherapeutic Platinum(IV) Prodrugs of Cisplatin as Multimodal Anticancer Agents. 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_5

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