Functionalized Graphene Oxide as Drug Delivery Systems for Platinum Anticancer Drugs
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Platinum-based agents are important drugs or drug candidates for cancer chemotherapy. Traditional platinum drugs including the globally approved cisplatin, carboplatin and oxaliplatin are neutral platinum (II) complexes with two amine ligands and two additional ligands that can be aquated for further binding with DNA. The platinum-DNA adducts can impede cellular process and lead to cellular apoptosis. Tumor resistance to platinum drugs has become a very challenging problem to overcome. Individualized cancer treatment using different strategies to circumvent the platinum-drug resistance in cancer patients is of great importance. Structural modification of traditional platinum drugs, combination therapy using platinum drugs with other agents and improved delivery of platinum drug to tumor sites are major strategies developed to overcome existed problems in chemotherapy using traditional platinum drugs. Platinum-based agents with respect to their structure, mechanism of action and strategies developed for improved efficacy in cancer treatment have been summarized in this paper with the perspective of developing new platinum drugs or platinum-based therapy for individualized cancer treatment. Keywords: Cancer chemotherapy, personalized medicine, platinum-based agents, platinum drug delivery, platinum drug resistance.
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Cisplatin, carboplatin, and oxaliplatin are the common platinum-based anticancer drugs widely used in the chemotherapeutic treatment of solid tumors in clinic. However, the comprehensive pharmacokinetics of platinum-based anticancer drugs has not been fully understood yet. This leads to many limitations for the further studies on their pharmacology and toxicology. In this study, we conduct a systemic evaluation on the pharmacokinetics of three platinum analogues at animal and cell levels, with quantification of both total platinum and intact drugs. A detailed animal study to address and compare the different pharmacokinetic behaviors of three platinum analogues has been conducted in three biological matrices: blood, plasma, and ultrafiltrate plasma. Carboplatin showed an obviously different pharmacokinetic characteristic from cisplatin and oxaliplatin. On the one hand, carboplatin has the highest proportion of Pt distribution in ultrafiltrate plasma. On the other hand, carboplatin has the highest intact drug exposure and longest intact drug elimination time in blood, plasma, and ultrafiltrate plasma, which may explain its high hematotoxicity. Additionally, the cellular and subcellular pharmacokinetics of oxaliplatin in two colon cancer HCT-116/LOVO cell lines has been elucidated for the first time. The biotransformation of intact oxaliplatin in cells was rapid with a fast elimination, however, the generated platinum-containing metabolites still exist within cells. The distribution of total platinum in the cytosol is higher than in the mitochondria, followed by the nucleus. Enrichment of platinum in mitochondria may affect the respiratory chain or energy metabolism, and further lead to cell apoptosis, which may indicate mitochondria as another potential target for efficacy and toxicity of oxaliplatin.
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We have previously confirmed the in vitro activity of cisplatin and carboplatin against human melanoma cell lines. Both drugs are important components in the chemotherapy used in our service for advanced metastatic melanoma. In this communication we report the in vitro activity of oxaliplatin against human melanoma cell lines in comparison with cisplatin and carboplatin. Oxaliplatin was found to be active against C32 and G361 cell lines with IC50 values of 49.48 and 9.07 μM (1 h exposure), 9.47 and 1.30 μM (4 h exposure), and 0.98 and 0.14 μM (24 h exposure), respectively. The cytotoxic activity of oxaliplatin in this in vitro system appears to be significantly superior to that of carboplatin. Its activity becomes comparatively closer to that of cisplatin as exposure time increases. Indeed at a 24 h exposure oxaliplatin appears to be significantly more active than cisplatin against the G361 cell line (p=0.0343). Oxaliplatin merits evaluation in the clinic both as a single agent and in combination with other drugs active against melanoma.
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Abstract Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.
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Some of the platinum complexes such as Cisplatin, carboplatin, and oxaliplatin are the FDA-approved members of the platinum anticancer drug family. Cisplatin, as one of the leading metal-based drugs, is widely used in the treatment of cancer. Significant side effects and drug resistance, however, have limited its clinical applications. These compounds induce apoptosis in tumor cells by binding to nuclear DNA, forming a variety of structural adducts and triggering cellular responses. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. In this report we present the development of platinum complexes such as platinum(II)-amine complexes, platinum(IV)-amine complexes, multi nuclear platinum complexes and some other platinum complexes as anti-cancer agents, with the purpose of providing an insight into the benefits of, and reasons for, their success.
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The important progress in platinum drugs has been witnessed in past nearly half a century. On the one hand,new platinum drugs such as nedaplatin, oxaliplatin, lobaplatin and sunpla have continuously emerged, and put into use in clinic after clinical trials were successfully completed. The analogues of cisplatin and carboplatin, the lipophilic and sterically hindered complexes and even some oral platinum complexes are in clinical trials, some of which will become new-type platinum drugs in the near future. On the other hand, combination of platinum with other anticancer drugs has significantly improved the anticancer efficacy and some important breakthroughs have been made in platinum-induced chemoresistance research.
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Background: The platinum (II) complexes as anticancer agents have been well explored for the development of novel analogs. Yet, none of them achieved clinical importance in oncology. At present, anticancer compounds containing platinum (II) complexes have been employed in the treatment of colorectal, lung, and genitourinary tumors. Among the platinum-based anticancer drugs, Cisplatin (cis-diamine dichloroplatinum (II), cis-[Pt(NH3)2Cl2]) is one of the most potent components of cancer chemotherapy. The nephrotoxicity, neurotoxicity and ototoxicity, and platinum compounds associated resistant cancer are some major disadvantages. Objective: With the rapidly growing interest in platinum (II) complexes in tumor chemotherapy, researchers have synthesized many new platinum analogs as anticancer agents that show better cytotoxicity, and less off-target effects with less cellular resistance. This follows the introduction of oxaliplatin, water-soluble carboplatin, multinuclear platinum and newly synthesized complexes, etc. Method: This review emphasizes recent advancements in drug design and development, the mechanism of platinum (II) complexes, their stereochemistry, current updates, and biomedical applications of platinum-based anticancer agents. Conclusion: In the last few decades, the popularity of platinum complexes as potent anti-cancer agents has risen as scientists have synthesized many new platinum complexes that exhibit better cytotoxicity coupled with less off-target effects.
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This chapter contains sections titled: Introduction, Anti-tumor Activity of Cisplatin Anti-tumor Activity of Carboplatin, Oxaliplatin and Nedaplatin Mechanism of Action of Cisplatin Mechanism of Action of Carboplatin, Oxaliplatin and Nedaplatin Activation of trans Geometry Polynuclear Platinum Compounds Platinum(IV) Compounds Targeted Analogues Anti-viral Activity Combinations of Platinum Complexes with Other Agents Conclusions Acknowledgements References
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