RESUMO
The impact of kinetic lability or reactivity on inâ vitro cytotoxicity, stability in plasma, inâ vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a OËO ß-diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3 )2 Pt(L1-H)]NO3 and [(DACH)Pt(L1-H)]NO3 (L1=4,4,4-trifluoro-1-ferrocenylbutane-1,3-dione, DACH=1R,2R-cyclohexane-1,2-diamine) containing an electron deficient [L1-H]- OËO leaving ligand and [(NH3 )2 Pt(L2-H)]NO3 and [(DACH)Pt(L2-H)]NO3 (L2=1-ferrocenylbutane-1,3-dione) containing an electron-rich [L2-H]- OËO leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron-withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite inâ vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on inâ vitro and inâ vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.
Assuntos
Antineoplásicos , Cicloexilaminas , Neoplasias , Radiossensibilizantes , Humanos , Animais , Camundongos , Platina , Ligantes , Compostos Organoplatínicos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
Even in the modern era of precision medicine and immunotherapy, chemotherapy with platinum (Pt) drugs remains among the most commonly prescribed medications against a variety of cancers. Unfortunately, the broad applicability of these blockbuster Pt drugs is severely limited by intrinsic and/or acquired resistance, and high systemic toxicity. Considering the strong interconnection between kinetic lability and undesired shortcomings of clinical Pt drugs, we rationally designed kinetically inert organometallic Pt based anticancer agents with a novel mechanism of action. Using a combination of in vitro and in vivo assays, we demonstrated that the development of a remarkably efficacious but kinetically inert Pt anticancer agent is feasible. Along with exerting promising antitumor efficacy in Pt-sensitive as well as Pt-resistant tumors in vivo, our best candidate has the ability to mitigate the nephrotoxicity issue associated with cisplatin. In addition to demonstrating, for the first time, the power of kinetic inertness in improving the therapeutic benefits of Pt based anticancer therapy, we describe the detailed mechanism of action of our best kinetically inert antitumor agent. This study will certainly pave the way for designing the next generation of anticancer drugs for effective treatment of various cancers.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Platina/farmacologia , Platina/uso terapêutico , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Cinética , Linhagem Celular TumoralRESUMO
Cancer, which is characterized by uncontrolled proliferation of abnormal cells, is a leading cause of morbidity and mortality worldwide. Cytotoxic chemotherapy, especially with platinum drugs, remains the mainstay of cancer treatment in the clinical setting. Despite phenomenal success, small-molecule chemotherapeutic drugs suffer from some serious drawbacks. Lack of cancer selectivity and the ensuing side effects mar the therapeutic potential of these drugs. Glycoconjugation has emerged as an attractive strategy for imparting selectivity and improving pharmacokinetics of cytotoxic agents. In this review, we provide an overview of the glycoconjugation strategy and then illustrate the application of this strategy with the help of some concrete examples of platinum based glycoconjugates. At the end we discuss a few important aspects of these glycoconjugates which merit further investigations.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Platina , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glicoconjugados/farmacologiaRESUMO
Around 10 million fatalities were recorded worldwide in 2020 due to cancer and statistical projections estimate the number to increase by 60% in 2040. With such a substantial rise in the global cancer burden, the disease will continue to impose a huge socio-economic burden on society. Currently, the most widely used clinical treatment modality is cytotoxic chemotherapy using platinum drugs which is used to treat variety of cancers. Despite its clinical success, critical challenges like resistance, off-target side effects and cancer variability often reduce its overall therapeutic efficiency. These challenges require faster diagnosis, simultaneous therapy and a more personalized approach toward cancer management. To this end, small-molecule 'theranostic' agents have presented a viable solution combining diagnosis and therapy into a single platform. In this review, we present a summary of recent efforts in the design and optimization of metal-based small-molecule 'theranostic' anticancer agents. Importantly, we highlight the advantages of a theranostic candidate over the purely therapeutic or diagnostic agent in terms of evaluation of its biological properties.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Platina , Medicina de Precisão , Nanomedicina TeranósticaRESUMO
Chemotherapy is the primary treatment modality employed in the clinic for the treatment of cancer. Despite proven clinical success, adverse side effects are one of the drawbacks of this approach. The prodrug strategy has emerged as an alternative approach with the aim of alleviating these drawbacks. Prodrug activation is typically achieved by either endogenous or exogenous triggers. Exogenous triggers like light are appealing as they are independent of inherent patient and/or cancer-type variations. However, tissue penetration depth remains the Achilles' heel of this approach. In this context, usage of X-rays as the external trigger with infinite tissue penetration depth opens up exciting prospects in prodrug activation strategies.