Harnessing Structure-activity Relationship to Engineer a Cisplatin Nanoparticle for Enhanced Antitumor Efficacy

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jul 10

PMID 20616005

Citations 47

Authors

Abhimanyu S Paraskar

Shivani Soni

Kenneth T Chin

Padmaparna Chaudhuri

Katherine W Muto

Julia Berkowitz

Michael W Handlogten

Nathan J Alves

Basar Bilgicer

Daniela M Dinulescu

Raghunath A Mashelkar

Shiladitya Sengupta

Affiliations

Soon will be listed here.

Abstract

Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.

Citing Articles

Novel platinum therapeutics induce rapid cancer cell death through triggering intracellular ROS storm.

Liu Y, Yu D, Ge X, Huang L, Pan P, Shen H Biomaterials. 2024; 314:122835.

PMID: 39276409 PMC: 11560510. DOI: 10.1016/j.biomaterials.2024.122835.

Stability-Enhanced Cisplatin Gold Nanoparticles As Therapeutic Anticancer Agents.

Cho T, Reipa V, Gorham J, Pettibone J, Tona A, Johnston-Peck A ACS Appl Nano Mater. 2024; 7(1).

PMID: 38846932 PMC: 11155487. DOI: 10.1021/acsanm.3c04935.

Mitochondrial dysfunction route as a possible biomarker and therapy target for human cancer.

Al-Faze R, Ahmed H, El-Atawy M, Zagloul H, Alshammari E, Jaremko M Biomed J. 2024; 48(1):100714.

PMID: 38452973 PMC: 11743316. DOI: 10.1016/j.bj.2024.100714.

(Nano)platforms in bladder cancer therapy: Challenges and opportunities.

Ashrafizadeh M, Zarrabi A, Karimi-Maleh H, Taheriazam A, Mirzaei S, Hashemi M Bioeng Transl Med. 2023; 8(1):e10353.

PMID: 36684065 PMC: 9842064. DOI: 10.1002/btm2.10353.

A spotlight on alkaloid nanoformulations for the treatment of lung cancer.

S M S, Naveen N, Rao G, Gopan G, Chopra H, Park M Front Oncol. 2022; 12:994155.

PMID: 36330493 PMC: 9623325. DOI: 10.3389/fonc.2022.994155.

References

Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A . Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006; 12(4):1317-24. DOI: 10.1158/1078-0432.CCR-05-1634. View

Northfelt D, Martin F, Working P, Volberding P, Russell J, Newman M . Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi's sarcoma. J Clin Pharmacol. 1996; 36(1):55-63. DOI: 10.1002/j.1552-4604.1996.tb04152.x. View

Yuan F, Dellian M, Fukumura D, Leunig M, Berk D, Torchilin V . Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 1995; 55(17):3752-6. View

Go R, Adjei A . Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol. 1999; 17(1):409-22. DOI: 10.1200/JCO.1999.17.1.409. View

Knox R, Friedlos F, Lydall D, Roberts J . Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res. 1986; 46(4 Pt 2):1972-9. View

Davies M, Berners-Price S, Hambley T . Slowing of cisplatin aquation in the presence of DNA but not in the presence of phosphate: improved understanding of sequence selectivity and the roles of monoaquated and diaquated species in the binding of cisplatin to DNA. Inorg Chem. 2001; 39(25):5603-13. DOI: 10.1021/ic000847w. View

Moghimi S, Hunter A, Murray J . Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001; 53(2):283-318. View

Hongo A, Seki S, Akiyama K, Kudo T . A comparison of in vitro platinum-DNA adduct formation between carboplatin and cisplatin. Int J Biochem. 1994; 26(8):1009-16. DOI: 10.1016/0020-711x(94)90072-8. View

Leong C, Vidnovic N, DeYoung M, Sgroi D, Ellisen L . The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Invest. 2007; 117(5):1370-80. PMC: 1849987. DOI: 10.1172/JCI30866. View

10.

Rademaker-Lakhai J, Terret C, Howell S, Baud C, de Boer R, Pluim D . A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors. Clin Cancer Res. 2004; 10(10):3386-95. DOI: 10.1158/1078-0432.CCR-03-0315. View

11.

Kelland L . The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007; 7(8):573-84. DOI: 10.1038/nrc2167. View

12.

Huang H, Zhu L, Reid B, Drobny G, Hopkins P . Solution structure of a cisplatin-induced DNA interstrand cross-link. Science. 1995; 270(5243):1842-5. DOI: 10.1126/science.270.5243.1842. View

13.

Madias N, Harrington J . Platinum nephrotoxicity. Am J Med. 1978; 65(2):307-14. DOI: 10.1016/0002-9343(78)90825-2. View

14.

Choi H, Liu W, Misra P, Tanaka E, Zimmer J, Ipe B . Renal clearance of quantum dots. Nat Biotechnol. 2007; 25(10):1165-70. PMC: 2702539. DOI: 10.1038/nbt1340. View

15.

Avgoustakis K, Beletsi A, Panagi Z, Klepetsanis P, Karydas A, Ithakissios D . PLGA-mPEG nanoparticles of cisplatin: in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties. J Control Release. 2002; 79(1-3):123-35. DOI: 10.1016/s0168-3659(01)00530-2. View

16.

Fujiyama J, Nakase Y, Osaki K, Sakakura C, Yamagishi H, Hagiwara A . Cisplatin incorporated in microspheres: development and fundamental studies for its clinical application. J Control Release. 2003; 89(3):397-408. DOI: 10.1016/s0168-3659(03)00131-7. View

17.

Decuzzi P, Pasqualini R, Arap W, Ferrari M . Intravascular delivery of particulate systems: does geometry really matter?. Pharm Res. 2008; 26(1):235-43. DOI: 10.1007/s11095-008-9697-x. View

18.

Cuatrecasas M, Erill N, Musulen E, Costa I, Matias-Guiu X, Prat J . K-ras mutations in nonmucinous ovarian epithelial tumors: a molecular analysis and clinicopathologic study of 144 patients. Cancer. 1998; 82(6):1088-95. View

19.

Lin X, Zhang Q, Rice J, Stewart D, Nowotnik D, Howell S . Improved targeting of platinum chemotherapeutics. the antitumour activity of the HPMA copolymer platinum agent AP5280 in murine tumour models. Eur J Cancer. 2004; 40(2):291-7. DOI: 10.1016/j.ejca.2003.09.022. View

20.

Gratton S, Ropp P, Pohlhaus P, Luft J, Madden V, Napier M . The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci U S A. 2008; 105(33):11613-8. PMC: 2575324. DOI: 10.1073/pnas.0801763105. View