Platinum-based drugs for cancer therapy and anti-tumor strategies

Abstract

Platinum-based drugs cisplatin, carboplatin, and oxaliplatin are widely used for chemotherapeutic eradication of cancer. However, the side effects of platinum drugs, such as lack of selectivity, high systemic toxicity, and drug resistance, seriously limit their clinical application. With advancements in nanotechnology and chemical synthesis, Pt-based anti-cancer drugs have made great progress in cancer therapy in recent years. Many strategies relied on the anti-cancer mechanism similar to cisplatin and achieved some success by modifying existing platinum drugs. Pt-based nanodrugs, such as platinum nanoclusters, have novel anti-cancer mechanisms and great potential in tumor-targeted therapy and have shown promising results in clinical application. In this review, we systematically explored the development of first-line platinum chemotherapy drugs in the clinic and their anti-cancer mechanisms. We also summarize the progress of Pt-based anti-cancer drug application in cancer therapy, emphasizing their modification to enhance the anti-tumor effect. Finally, we address challenges faced by platinum chemotherapy drugs, especially Pt nanocluster-based nanodrugs, in cancer treatment. The new platinum drugs and their targeted modifications undoubtedly provide a promising prospect for improving the current anti-cancer treatments.

Keywords: Anti-cancer mechanism; Cancer therapy; Platinum nanoclusters; Platinum-based drugs; Systemic toxicity.

Figure 1

Summary of the action mechanism of cisplatin. (A) Mechanism of action of cisplatin comprising (i) cellular uptake, (ii) aquation/activation, (iii) DNA platination, and (iv) cellular processing leading to apoptosis. Adapted with permission from ref , copyright 2016 American Chemical Society. (B) Alternative effects of cisplatin. Other interesting mechanisms such as acidification of the cytoplasm, ER stress, disruption of RNA transcription, inhibition of important oncogenic proteins, and decrease in metabolic plasticity of cancer cells as well as changes in their mechanobiology. Adapted with permission from ref , copyright 2019 Royal Society of Chemistry.

Figure 2

Summary of the bio-conjunction targeting moiety to improve the anti-cancer efficiency of Pt drugs, (A) RGD peptide , (B) CPP peptide , (C) LHRH peptide , and (D) biotin . Adapted with permission from ref , copyright 2014 American Chemical Society, ref , copyright 2017 Royal Society of Chemistry, ref , copyright 2017 American Chemical Society and ref , copyright 2017 Royal Society of Chemistry, respectively.

Figure 3

Schematic illustration of GNC-based theranostic nanoplatform for tumor-targeted chemotherapy and fluorescence imaging. Adapted with permission from ref , copyright 2016 Ivyspring International Publisher.

Figure 4

Chemical synthesis of the platinum-tethered gold nanoparticles. Adapted with permission from ref , copyright 2010 American Chemical Society.

Figure 5

(A) Delivery system of gold-coated iron oxide nanoparticles functionalized with thiolated polyethylene glycol (PEG) linkers to which the active component of the anti-cancer drug cisplatin, [Pt(NH₃)₂]²⁺, is attached via the terminal carboxylate groups. (B) UV-Vis spectra of the four nanoparticles: FeNPs (blue), Au@FeNPs (orange), PEGylated Au@FeNPs (green), and Pt@Au@FeNPs (purple). (C) In vitro cytotoxicity of the nanoparticles in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-line A2780/cp70. Resistance factor (Rf) is defined as the IC₅₀ of the complex in the resistant line divided by the IC₅₀ of the complex in the sensitive line; any complex with an Rf less than 1 can overcome cisplatin resistance. Adapted with permission from ref , copyright 2012 Elsevier.

Figure 6

(A) Chemical structure of copolymers poly(methacrylic acid)-graft-poly(ethyleneglycol methacrylate) (p(MAA-g-EGMA)). (B) Schematic structure of the studied magnetic drug delivery systems. Evolution with time of (C) Tumor volume and (E)% weight change of mice (n=4) after i.v. injections with: saline (Control), nanocarriers without the drug (Blank), aqueous cisplatin solution (FD), cisplatin-loaded nanocarriers (PD), and cisplatin-loaded nanocarriers in the presence of an external magnetic field in the tumor area (PDMF). Arrows in (a) and (b) represent tail vein injection events. (D) Pictures of the tumors taken at the end of the study period are shown for comparison. (F) Spleen index of mice sacrificed at the end of the in vivo experiment. Adapted with permission from ref , copyright 2016 Elsevier.

Figure 7

(A) Schematic diagram of the preparation of SFN-CDDP-NPs for improved anti-tumor therapy. Adapted with permission from ref , copyright 2020 American Chemical Society. (B) Illustration of the redox-responsive nanoplatform, composed of Pt(IV) prodrug 5, Cys-8E polymer, and lipid-PEG, for in vivo Pt delivery and treatment of cisplatin-resistant tumors. Adapted with permission from ref , copyright 2018 American Chemical Society. (C) Schematic illustration of phospholipid-mimic CBP-LA conjugates that self-assemble into micelle-like nanoparticles and the possible mechanism of their anti-cancer activity. Adapted with permission from ref , copyright 2018 Royal Society of Chemistry.

Figure 8

Illustration of a possible mechanism accounting for FePt@CoS₂ yolk-shell nanocrystals killing HeLa cells. After cellular uptake, FePt nanoparticles were oxidized to generate Fe³⁺ (omitted for clarity) and Pt²⁺ ions (yellow). The Pt²⁺ ions enter into the nucleus (and mitochondria), bind to DNA, and lead to apoptosis of the HeLa cell. Adapted with permission from ref , copyright 2008 American Chemical Society.

Figure 9

Schematic of apoptosis mechanism of Pt NCs. Abundant oxidized Pt ions and Pt NCs coordinate the DNA damage activating the p53 pathway. Adapted with permission from ref , copyright 2017 Elsevier.

Figure 10

Schematic illustration of GSH-chelated Pt molecule (Pt₆GS₄) as a potent anti-cancer agent. High efficacy for anti-cancer treatment and lower systemic toxicity were achieved by Pt₆GS₄ both in vitro and in vivo, compared to carboplatin at the same dosage. Adapted with permission from ref , copyright 2020 Wiley.

Figure 11

Design and characterization of HCC-targeted pH-sensitive Pt nanocluster assembly (Pt-NA). (A) Schematic representation of Pt-NA synthesis, targeted HCC uptake, and intracellular Pt ion release. (B) TEM image of the synthesized Pt NCs. (C) TEM image of Pt-NA. (D) High-resolution TEM image of Pt-NA. (E) Photographs of Pt-NA in pH 6.0 and 7.4. (F) The transmittance of a suspension of Pt-NA as a function of pH. (G) DLS size measurement of Pt-NA (0.1 mg mL^-1) as a function of pH. (H) pH profile of Pt-NA by acid-base titration. Adapted with permission from ref , copyright 2016 American Chemical Society.

Figure 12

(A) Schematic representation of a novel strategy based on tuning anionic geometry for the formation of PN. (B) Schematic representation of the caged PN mixed with a tumor-penetrating peptide to target the tumor and kill malignant cells by shedding the outer PEG corona to exert tumor-inside activation. Adapted with permission from ref , copyright 2013 Wiley.