A spermine-conjugated lipophilic Pt(<scp>iv</scp>) prodrug designed to eliminate cancer stem cells in ovarian cancer

Stilgenbauer, Morgan; Jayawardhana, Amarasooriya M. D. S.; Datta, Payel; Yue, Zhizhou; Gray, Michael; Nielsen, Frederick; Bowers, David J.; Xiao, Haihua; Zheng, Yao‐Rong

doi:10.1039/c9cc02081k

Cited by 23 publications

(11 citation statements)

References 15 publications

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“…Following a different approach, the incorporation of a maleimide fragment enabled specific interactions with proteins (e.g., addition to thiol residues) for compounds showing a promising anticancer activity in vivo [261,268,369]. The conjugation with suitable targeting groups, to enhance the pharmacological performance, can be achieved via modification of either the axial carboxylato co-ligand [367,370] or the carbamato ligand itself [272,371,372]. Remarkably, all of these Pt(IV) complexes are stable for several hours or even days in physiological aqueous solutions [260,261,263,272].…”

Section: Other Applicationsmentioning

confidence: 99%

Recent Advances in the Chemistry of Metal Carbamates

et al. 2020

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Following a related review dating back to 2003, the present review discusses in detail the various synthetic, structural and reactivity aspects of metal species containing one or more carbamato ligands, representing a large family of compounds across all the periodic table. A preliminary overview is provided on the reactivity of carbon dioxide with amines, and emphasis is given to recent findings concerning applications in various fields.

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Section: Other Applicationsmentioning

confidence: 99%

Recent Advances in the Chemistry of Metal Carbamates

et al. 2020

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“…Current treatment for ovarian cancer patients leads to a high initial response rate, but most patients develop progressive resistance to disease within a few months of diagnosis. [33][34][35][36][37] Therefore, there is an urgent need for alternative drugs to treat drug-resistant ovarian tumors. Our works suggest that novel nanoparticles BAF312@CaP-NPs deserve further evaluation for the treatment of this tumor type.…”

Section: Discussionmentioning

confidence: 99%

<p>Nanoparticle BAF312@CaP-NP Overcomes Sphingosine-1-Phosphate Receptor-1-Mediated Chemoresistance Through Inhibiting S1PR1/P-STAT3 Axis in Ovarian Carcinoma</p>

Gong

Dong

Wang

et al. 2020

IJN

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Purpose Platinum/paclitaxel-based chemotherapy is the strategy for ovarian cancer, but chemoresistance, inherent or acquired, occurs and hinders therapy. Therefore, further understanding of the mechanisms of drug resistance and adoption of novel therapeutic strategies are urgently needed. Methods In this study, we report that sphingosine-1-phosphate receptor-1 (S1PR1)-mediated chemoresistance for ovarian cancer. Then we developed nanoparticles with a hydrophilic PEG2000 chain and a hydrophobic DSPE and biodegradable CaP (calcium ions and phosphate ions) shell with pH sensitivity as a delivery system (CaP-NPs) to carry BAF312, a selective antagonist of S1PR1 (BAF312@CaP-NPs), to overcome the cisplatin (DDP) resistance of the ovarian cancer cell line SKOV3DR. Results We found that S1PR1 affected acquired chemoresistance in ovarian cancer by increasing the phosphorylated-signal transduction and activators of transcription 3 (P-STAT3) level. The mean size and zeta potential of BAF312@CaP-NPs were 116 ± 4.341 nm and −9.67 ± 0.935 mV, respectively. The incorporation efficiency for BAF312 in the CaP-NPs was 76.1%. The small size of the nanoparticles elevated their enrichment in the tumor, and the degradable CaP shell with smart pH sensitivity of the BAF312@CaP-NPs ensured the release of BAF312 in the acidic tumor niche. BAF312@CaP-NPs caused substantial cytotoxicity in DDP-resistant ovarian cancer cells by downregulating S1PR1 and P-STAT3 levels. Conclusion We found that BAF312@CaP-NPs act as an effective and selective delivery system for overcoming S1PR1-mediated chemoresistance in ovarian carcinoma by inhibiting S1PR1 and P-STAT3.

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“…For example, Pt(IV) prodrugs, which release cisplatin in cancer cells, have been developed. [ 9–12 ] Pt(IV) prodrugs are more resistant to ligand substitution reactions than cisplatin because Pt(IV) centers are saturated and kinetically more inert. [ 1 ] Thus, Pt(IV) can minimize unwanted side reactions with biomolecules prior to DNA binding.…”

Section: Figurementioning

confidence: 99%

Fighting against Drug‐Resistant Tumors using a Dual‐Responsive Pt(IV)/Ru(II) Bimetallic Polymer

et al. 2020

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First, proteins such as serum albumin in blood deactivate cisplatin. [5] Second, cisplatin cannot be efficiently taken up by cisplatin-resistant cancer cells. [6] Third, intracellular biomolecules such as metallothionein (MT) and glutathione (GSH) may strongly bind and sequester cisplatin. [7] Fourth, the DNA of cancer cells that are damaged by cisplatin, can be repaired by proteins. [8] All these deactivation pathways hinder the curative effects of cisplatin. Some strategies have been developed to overcome the abovementioned deactivation pathways. For example, Pt(IV) prodrugs, which release cisplatin in cancer cells, have been developed. [9-12] Pt(IV) prodrugs are more resistant to ligand substitution reactions than cisplatin because Pt(IV) centers are saturated and kinetically more inert. [1] Thus, Pt(IV) can minimize unwanted side reactions with biomolecules prior to DNA binding. Another strategy to overcome deactivation is to combine cisplatin with other anticancer agents such as paclitaxel, 5-fluorouracil, gemcitabine or ruthenium complexes. [13-16] Mixtures of anticancer agents possess multiple targets and actions; this strategy strengthens the therapeutic effects via the different anticancer mechanisms of the different agents. [14] A third strategy to overcome deactivation is to use nanocarriers for the delivery of cisplatin. [17,18] Some Drug resistance is a major problem in cancer treatment. Herein, the design of a dual-responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) to treat cisplatin-resistant tumors in a patient-derived xenograft (PDX) model is reported. PolyPt/Ru is an amphiphilic ABA-type triblock copolymer. The hydrophilic A blocks consist of biocompatible poly(ethylene glycol) (PEG). The hydrophobic B block contains reduction-responsive Pt(IV) and red-light-responsive Ru(II) moieties. PolyPt/Ru self-assembles into nanoparticles that are efficiently taken up by cisplatin-resistant cancer cells. Irradiation of cancer cells containing PolyPt/Ru nanoparticles with red light generates 1 O 2 , induces polymer degradation, and triggers the release of the Ru(II) anticancer agent. Meanwhile, the anticancer drug, cisplatin, is released in the intracellular environment via reduction of the Pt(IV) moieties. The released Ru(II) anticancer agent, cisplatin, and the generated 1 O 2 have different anticancer mechanisms; their synergistic effects inhibit the growth of drugresistant cancer cells. Furthermore, PolyPt/Ru nanoparticles inhibit tumor growth in a PDX mouse model because they circulate in the bloodstream, accumulate at tumor sites, exhibit good biocompatibility, and do not cause side effects. The results demonstrate that the development of stimuli-responsive multi-metallic polymers provides a new strategy to overcome drug resistance.

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A spermine-conjugated lipophilic Pt(iv) prodrug designed to eliminate cancer stem cells in ovarian cancer

Abstract: A spermine-conjugated lipophilic Pt(iv) prodrug is designed to induce mitochondrial damage and eliminate ovarian cancer stem cells.

Cited by 23 publications

References 15 publications

Recent Advances in the Chemistry of Metal Carbamates

Recent Advances in the Chemistry of Metal Carbamates

<p>Nanoparticle BAF312@CaP-NP Overcomes Sphingosine-1-Phosphate Receptor-1-Mediated Chemoresistance Through Inhibiting S1PR1/P-STAT3 Axis in Ovarian Carcinoma</p>

Fighting against Drug‐Resistant Tumors using a Dual‐Responsive Pt(IV)/Ru(II) Bimetallic Polymer

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