The Prodrug Platin‐<i>A</i>: Simultaneous Release of Cisplatin and Aspirin

Pathak, Rakesh; Marrache, Sean; Choi, Joshua H.; Berding, Trenton B.; Dhar, Shanta

doi:10.1002/ange.201308899

Cited by 71 publications

(51 citation statements)

References 30 publications

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“…Recently, a Pt(II) compound, mtPt, with a mitochondria-targeting peptide for attacking mtDNA, was reported (7). Pt(IV) prodrugs are advantageous over the Pt(II) counterparts because of their greater stability and local activation, which allow a greater proportion of the active drug at the target site(s) (8). Mitochondrial functions including respiration are greatly reduced in cancer cells, and tumor microenvironments differ greatly from that of normal tissues.…”

Section: Resultsmentioning

confidence: 99%

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Marrache

Pathak

Dhar

2014

Proc. Natl. Acad. Sci. U.S.A.

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226

209

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Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strainpromoted alkyne-azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatinbased therapy.click chemistry | brain cancer | OXPHOS | pharmacokinetics T he cellular powerhouse, mitochondria, are implicated in the process of carcinogenesis because of their vital roles in energy production and apoptosis. Mitochondria are the key players in generating the cellular energy through oxidative phosphorylation (OXPHOS) that produces reactive oxygen species (ROS) as by-products. Mitochondrial DNA (mtDNA) plays significant roles in cell death and metastatic competence. The close proximity of mtDNA to the ROS production site makes this genome vulnerable to oxidative damage. Mitochondrial dysfunction and associated mtDNA depletion possibly reversibly control epigenetic changes in the nucleus that contributes to cancer development (1). Thus, targeting mtDNA could lead to novel and effective therapies for aggressive cancers. Cisplatin, a Food and Drug Administration-approved chemotherapeutic agent, is most extensively characterized as a DNA-damaging agent and the cytotoxicity of cisplatin is attributed to the ability to form interstrand and intrastrand nuclear DNA (nDNA) cross-links (2). The nucleotide excision repair (NER) pathway plays major roles in repairing cisplatin-nDNA adducts (3). Resistance to cisplatin can result fr...

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Section: Resultsmentioning

confidence: 99%

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Marrache

Pathak

Dhar

2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

226

209

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“…One approach is design and development of new Pt complexes that modulate the molecular process and pathways associated with tumor suppression. 8,9 Mitochondria represent interesting targets for drug development. A wide range of pathologies including cardiovascular disorders, 10 diabetes, 11 neurodegenerative diseases, 12,13 and cancers are related with mitochondrial dysfunction.…”

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confidence: 99%

Mitochondria-Localized Fluorescent BODIPY-Platinum Conjugate

Sun

Guan

Zheng

et al. 2015

ACS Med. Chem. Lett.

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A convenient synthesis of a BODIPY (1,3,5,7-tetramethyl-8-(4-pyridyl)-4,4′-difluoroboradiazaindacene) labeled platinum compound (BODIPY-Pt) was developed by direct conjugation of cisplatin with the pyridine group of BODIPY. The membrane permeability and selective uptake of BODIPY-Pt in the mitochondria was studied using confocal laser scanning microscopy (CLSM). The fluorescent BODIPYPt conjugate showed high cellular proliferation inhibition against human cervical carcinoma (HeLa) and human breast cancer (MCF-7) cells, with half maximal inhibitory concentrations (IC 50 ) of 27.37 and 12.14 μM, respectively. This work highlights the potential of using BODIPY labeled Pt compounds to realize the visualization of Pt distribution in living cells.

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“…Absorbance values were normalized to DMSO-containing control wells and plotted as concentration of test compound versus % cell viability. IC 50 and IC 20 values were interpolated from the resulting dose-dependent curves. The IC 50 and IC 20 values correspond to the concentration required to decrease cell viability by 50% or 20% and were calculated from dose-response curves.…”

Section: Cytotoxicity Mtt Assaymentioning

confidence: 99%

“…IC 50 and IC 20 values were interpolated from the resulting dose-dependent curves. The IC 50 and IC 20 values correspond to the concentration required to decrease cell viability by 50% or 20% and were calculated from dose-response curves. The reported IC 50 values are the average of three independent experiments.…”

Section: Cytotoxicity Mtt Assaymentioning

confidence: 99%

“…Encouragingly, some metal-NSAID complexes exhibit greater cytotoxicity than cisplatin. A recent comprehensive review It should be noted that several metal-NSAIDs have been previously reported, and their binding to biomolecules such as DNA and human serum albumin (HSA) has been well characterized using spectroscopic methods [48][49][50][51][52]. In general, metal-NSAID complexes display stronger binding to biomolecules than the corresponding free NSAID.…”

Section: Introductionmentioning

confidence: 99%

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A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

2017

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Cancer stem cells (CSCs) are thought to be responsible for cancer relapse. CSCs are a subtype of cancer cells with the ability to differentiate, self-renew, and form secondary or tertiary tumors. Current cancer treatments-including chemotherapy, radiation, and surgery-effectively remove bulk cancer cells but are unable to eliminate CSCs. Here, we present the synthesis, characterization, and anti-CSC properties of a cobalt(III)-cyclam complex bearing two tolfenamic acid moieties, 3. Notably, 3 displays sub-micromolar potency towards breast CSCs and bulk breast cancer cells. Detailed mechanistic studies show that 3 is taken up readily by breast CSCs, enters the nucleus, causes DNA damage, and induces caspase-dependent apoptosis. Furthermore, 3 inhibits cyclooxygenase-2 (COX-2) expression in CSCs. The mechanism of action of 3 is similar to that of a naproxen-appended cobalt(III)-cyclam complex, 1 recently reported by our group. The advantage of 3 over 1 is that it has the potential to remove whole tumor populations (bulk cancer cells and CSCs) with a single dose.

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The Prodrug Platin‐A: Simultaneous Release of Cisplatin and Aspirin

Cited by 71 publications

References 30 publications

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Mitochondria-Localized Fluorescent BODIPY-Platinum Conjugate

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

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