Peptide Targeting of Platinum Anti-Cancer Drugs (original) (raw)
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Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum
Journal of Inorganic and Organometallic Polymers and Materials, 2007
Cancerous diseases, together with cardiac afflictions, account for the predominant causes of death among the adult population of the Western world. The classical platinum drugs, with cisplatin as their parent, have established themselves for years as leading components in the oncologist's arsenal of antitumor agents. As with most other antineoplastic drugs, however, incisive pharmacological deficiencies, notably excessive systemic toxicity and induction of drug resistance, have severely curtailed their overall efficaciousness. With the objective of overcoming these counterproductive deficiencies, the technique of polymer-drug conjugation, representing an advanced modality of drug delivery, has been developed in recent years to high standards worldwide. In a drug conjugate, water-soluble macromolecular carrier constructs designed in compliance with stringent pharmacological specifications are covalently, yet bioreversibly, interconnected with the bioactive agent. As a macromolecule following a pharmacokinetic pathway different from that of non-polymeric compounds, the conjugate acts as a pro-drug favorably transporting the agent through the various body compartments to, and into, the target cell, where the agent is enzymatically or hydrolytically separated from the carrier for its biological action. In the authors' laboratories the conjugation strategy has been adopted as the primary tool for drug efficacy enhancement. The present paper describes a special type of platinum complex carrier-bound via dicarboxymetal chelation, synthesized from carboxyl-functionalized polyamide-type carriers by platination with trans-1,2-diaminocyclohexanediaquaplatinum(II) dinitrate. In a series of in vitro tests antiproliferative activities have been determined against several human cancer cell lines. Whereas no improvements are observed in tests against a colorectal cancer, outstanding findings of the screening program include a 10-to 100-fold increase in cell-killing performance of the conjugates relative to the (non-polymeric) cisplatin standard against the HeLa adenocarcinoma, and distinctly reduced resistance factors (again, relative to cisplatin) in tests against the A2780 and A2780-cis pair of ovarian cell lines. These findings augur well for future developments of this class of platinum drugs. This article is dedicated to Professor Astruc.
Cancer Science, 2010
We have recently synthesized a new platinum derivative, poly (c, L-glutamic acid)-cisplatin conjugate (c-PGA-CDDP), and shown that it displayed remarkable antitumor activity against breast tumor in a mouse model. The purpose of this study is to systematically compare this new drug with three platinum derivatives currently used in the clinic: cisplatin, carboplatin and oxaliplatin. Here, we show that c-PGA-CDDP displays impressive antitumor activity over the current clinically used platinum drugs. More interestingly and more importantly, c-PGA-CDDP conjugate significantly reduces cytotoxicity, mitigates oxidative stress and improves antioxidative capability in vivo. Animals treated with c-PGA-CDDP display the same profile of body weight as the control animals, while the tumors in c-PGA-CDDP-treated animals are significantly suppressed compared with those treated with carboplatin and oxaliplatin. Our data suggest that c-PGA could be used as an effective carrier for drug delivery and that c-PGA-CDDP conjugate may have potential therapeutic applications in human cancers that are sensitive to treatment with CDDP-based chemotherapy such as ovarian cancer. (Cancer Sci 2010; 101: 2476-2482 T he cis-dichlorodiammineplatinum (II) (CDDP or cisplatin) is one of the most widely used and most effective cytotoxic agents in the clinical treatment of many different malignancies. It can be used alone or in combination with other antitumor drugs to treat a wide spectrum of human tumors including breast, liver, lung, head and neck, ovarian, testicular, bladder, small-cell and non-small-cell lung cancers. (1) However, its therapeutic efficacy is restricted by highly toxic side effects, such as nausea, ear damage, vomiting and especially the persistence of severe nephrotoxicity. (2) The severe side effects of cisplatin treatment have stimulated research toward developing less toxic CDDP analogue with enhanced antitumor activity. The modified platinum derivative carboplatin is more easily used in combination therapy and in ovarian cancer treatment. However, hematological adverse effects are more frequent with carboplatin than with cisplatin. (5) In addition, carboplatin still needs to be administrated intravenously. Oxaliplatin is the third generation of platinum drugs and shows a wide antitumor effect both in vitro and in vivo, (7) and is currently used in clinics as a first line treatment for metastatic colorectal cancer. The neuropathic and nephrotoxic (10) side effects of oxaliplatin are milder than cisplatin and carboplatin. However, oxaliplatin may cause severe allergic reactions. These allergic reactions may happen within a few minutes and may even cause death.
International Journal of Nanomedicine, 2010
Due to their unique properties, Anticancer dendrimer-based drugs have been displaying promising results in both in vitro and in vivo in the treatment of cancerous cells, as compared to the traditional polymers. In this report, two conjugates (G1+Pt and G2+Pt) of cisplatin [cis-diaminedichloroplatinum; (CDDP)] with two generations (G1, G2) of a biocompatible anionic dendrimer were prepared in an aqueous media. Their potential cytotoxic effects, in two sensitive cancer cell lines HT1080 and CT26 together with one resistant cancer cell line SKOV3, using MTT (methyl thiazolyl tetrazolium) assay were examined. Hemolytic impacts and cell death mechanisms of the conjugates on human blood and HT1080 cell line were also investigated. The conjugate G2+Pt showed greater toxicity up to 9× and 2× in the sensitive and resistant cell lines (IC 50 comparison, inhibitory concentration) respectively when compared to the parent drug. The G1+Pt conjugate showed greater toxicity only in the sensitive HT1080 (2×) and CT26 (3.7×) cell lines. Moreover, the G1+Pt conjugate was less toxic approximately one third of the cisplatin in SKOV3 after 48 hrs of incubation. In summary, the G2+Pt conjugate had greater toxicity than the G1+Pt conjugate and cisplatin, based on the in vitro results. Approximately the same hemolysis behavior was observed for both conjugates and cisplatin. Both apoptosis and necrosis mechanisms (about 2× more than cisplatin) were attributed to conjugates and cisplatin in a direct correlation between the concentration and the degree of cell death. In conclusion, these conjugates with such high potency and minimum hemolysis would be suitable candidates for use against these cancerous cell lines as efficient and novel antitumor agents.
Molecular Pharmacology, 2003
The antitumor and cellular pharmacological properties of the trans-Pt(IV) complex, trans-[PtCl 2 (OH) 2 (dimethylamine)(isopropylamine)] (compound 2) has been evaluated in comparison with its corresponding trans-Pt(II) counterpart, trans-[PtCl 2 (dimethylamine)(isopropylamine)] (compound 1). The results reported here indicate that compound 2 markedly circumvents cisplatin resistance in 41McisR and CH1cisR ovarian tumor cell lines endowed with different mechanisms of resistance (decreased platinum accumulation and enhanced DNA repair/tolerance, respectively). However, compound 1 is able to circumvent cisplatin resistance only in CH1cisR cells. Interestingly, at equitoxic concentrations, compounds 1 and 2 induce a higher amount of apoptotic cells than cisplatin in CH1cisR cells. Moreover, the number of apoptotic cells induced by compounds 1 and 2 correlates with their ability to form DNA interstrand crosslinks in CH1cisR cells. Although compounds 1 and 2 showed remarkable cytotoxic activity, only compound 2 was able to inhibit the growth of CH1 human ovarian carcinoma xenografts in mice. Binding studies with serum albumin indicate that compound 1 possesses a much higher reactivity against albumin than compound 2. Moreover, the level of binding of compound 1 to plasma proteins during the period 15 min to 1 h after administration to mice (15 mg/kg, i.p.) is 2.5-fold higher than that of compound 2. Therefore, the lack of in vivo antitumor activity shown by compound 1 might be related to its extracellular inactivation before reaching the tumor site because of its high rate of binding to plasma proteins. This work was supported by Spanish Comisión Interministerial de Ciencia y Tecnologica grant SAF00-0029. Support and sponsorship by Cost Actions D20/0001/00 and D20/0003/00 is kindly acknowledged. An institutional grant from Fundación Ramón Areces is also acknowledged.
Molecular Pharmacology, 2003
The antitumor and cellular pharmacological properties of the trans-Pt(IV) complex, trans-[PtCl 2 (OH) 2 (dimethylamine)(isopropylamine)] (compound 2) has been evaluated in comparison with its corresponding trans-Pt(II) counterpart, trans-[PtCl 2 (dimethylamine)(isopropylamine)] (compound 1). The results reported here indicate that compound 2 markedly circumvents cisplatin resistance in 41McisR and CH1cisR ovarian tumor cell lines endowed with different mechanisms of resistance (decreased platinum accumulation and enhanced DNA repair/tolerance, respectively). However, compound 1 is able to circumvent cisplatin resistance only in CH1cisR cells. Interestingly, at equitoxic concentrations, compounds 1 and 2 induce a higher amount of apoptotic cells than cisplatin in CH1cisR cells. Moreover, the number of apoptotic cells induced by compounds 1 and 2 correlates with their ability to form DNA interstrand crosslinks in CH1cisR cells. Although compounds 1 and 2 showed remarkable cytotoxic activity, only compound 2 was able to inhibit the growth of CH1 human ovarian carcinoma xenografts in mice. Binding studies with serum albumin indicate that compound 1 possesses a much higher reactivity against albumin than compound 2. Moreover, the level of binding of compound 1 to plasma proteins during the period 15 min to 1 h after administration to mice (15 mg/kg, i.p.) is 2.5-fold higher than that of compound 2. Therefore, the lack of in vivo antitumor activity shown by compound 1 might be related to its extracellular inactivation before reaching the tumor site because of its high rate of binding to plasma proteins. This work was supported by Spanish Comisión Interministerial de Ciencia y Tecnologica grant SAF00-0029. Support and sponsorship by Cost Actions D20/0001/00 and D20/0003/00 is kindly acknowledged. An institutional grant from Fundación Ramón Areces is also acknowledged.
Synthesis and in Vitro Antitumor Activity of Oligonucleotide-Tethered and Related Platinum Complexes
Journal of Medicinal Chemistry, 2001
Three classes of hydroxy-tethered platinum(II) complexes have been synthesized from K 2 PtCl 4 and appropriate amino alcohols. A sequence of selective oxidation and hydrolysis has been developed to prepare hydroxy-tethered platinum(IV) complexes. A novel procedure for the synthesis of amminetrichloroplatinate(II) anion has been generated and used to synthesize a number of monohydroxy-tethered nonchelating platinum complexes. These tethered platinum complexes, including hydroxy-tethered, phosphoramidite-tethered, and monodeoxyribonucleotide-tethered platinum(II) and -(IV) complexes, have been examined in vitro for antitumor activity in both leukemia and ovarian cancer cell lines. Activity of some of these complexes was similar to cis-platin, and most of them showed much better potency than carboplatin. We observed an interesting structure-activity correlation for platinum(II) complexes for both PA-1 and SK-OV-3 ovarian cancer cell lines. However, platinum(IV) complexes showed much more diversified response among cancer cell lines studied. We observed enhanced selectivity among different cancer cell lines for some agents. The most promising is the monodeoxyribonucleotidetethered platinum(IV) complex, which is the first analogue of the conjugates between a platinum fragment and monodeoxyribonucleotides, showing antitumor activity and selectivity among the cell lines. Finally, the p53 status of the cells appears to contribute to the effectiveness of these agents in that cells harboring wild-type p53 appear to be more sensitive to these agents.
Journal of Medicinal Chemistry, 2019
solubilities and pharmacokinetics. 8,9 Notwithstanding, the design and development of new single cytostatics that simultaneously affect more distinct oncogenic targets appears to be a promising strategy which is more profitable in comparison with the development of a combination of two or more drugs. One approach to designing multi-action cytotoxic platinum agents is based on Pt(IV) prodrugs that simultaneously release, after their reduction inside the cancer cell an active Pt(II) drug as well as bioactive moieties. These six-coordinate octahedral complexes are derivatives of square planar Pt(II) complexes containing axial ligands that can enhance hydrophobicity and consequently cellular accumulation, increase solubility, modify rates of reduction, and affect cellular target(s) other than DNA. 11 After they enter the tumor cell with the internal hypoxic environment, these inert Pt(IV) prodrugs are activated by reduction releasing the cytotoxic Pt(II) complex and the two axial bioactive ligands that can affect different intracellular targets and act by MoA(s) different from that of the Pt(II) complex. 12 Unquestionable advantages of these Pt(IV) prodrugs are; (i) they contain the combination of different drugs, each acting by a different MoA, in a single molecule with a single pharmacokinetic profile; (ii) they are kinetically inert in comparison with their Pt(II) counterparts, minimizing undesirable interactions with nucleophiles in extracellular milieu, which may reduce side effects, and enhance bioavailability; (iii) they can be administered orally. 13,14 A number of novel Pt(IV) prodrugs that simultaneously release, besides active Pt(II) complex, one or more different bioactive moieties inside the cancer cell were introduced (see for instance Refs. 15-25). Their cytotoxicity against cancer cells in vitro and in some cases also in vivo was significantly better than that of cisplatin or its clinically used derivatives. Quite recently, a novel