Ultrasmall iron oxide nanoparticles cisplatin (IV) prodrug nanoconjugate: ICP-MS based strategies to evaluate the formation and drug delivery capabilities in single cells

Turiel-Fernández, Daniel; Gutierrez-Romero, Lucia; Corte‐Rodríguez, Mario; Bettmer, Jörg; Montes-Bayón, Marı́a

doi:10.1016/j.aca.2021.338356

Cited by 40 publications

(29 citation statements)

References 32 publications

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“…This concentration increased significantly (by about fivefold) when the cells were left to stand for 3 h in drug-free media (t = 3 h), reaching levels of approximately 1300 ng Pt/mg DNA, which represented about 60% of the Pt taken up. These results can be explained by the time-dependent release of cisplatin from the Pt(IV)-FeNPs in the cell cytosol, as previously observed in model solutions [ 23 ]. In the case of the OVCAR-3 cell line, despite the fact that the cell uptake was significantly lower, the DNA-bound Pt concentration (28 ng Pt/mg DNA) after 24 h exposure also corresponded to approximately 10% of the concentration taken up (1.6 fg/cell).…”

Section: Resultssupporting

confidence: 77%

“…The excess of the prodrug was eliminated by ultracentrifugation using a 3000 Da Ultra-15 MWCO centrifugal filter. The quantification of the level of loading of the prodrug onto the particles was conducted with HPLC-ICP-MS by monitoring Pt and Fe simultaneously [ 23 ]. Each batch of modified nanoparticles was used for 2 weeks and then discarded.…”

Section: Methodsmentioning

confidence: 99%

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Cellular Toxicity Mechanisms and the Role of Autophagy in Pt(IV) Prodrug-Loaded Ultrasmall Iron Oxide Nanoparticles Used for Enhanced Drug Delivery

et al. 2021

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Ultrasmall iron oxide nanoparticles (<10 nm) were loaded with cis-diamminetetrachloroplatinum (IV), a cisplatin (II) prodrug, and used as an efficient nanodelivery system in cell models. To gain further insight into their behavior in ovarian cancer cells, the level of cellular incorporation as well as the platination of mitochondrial and nuclear DNA were measured using inductively coupled plasma mass spectrometry (ICP-MS) strategies. Quantitative Pt results revealed that after 24 h exposure to 20 µM Pt in the form of the Pt(IV)-loaded nanoparticles, approximately 10% of the incorporated Pt was associated with nuclear DNA. This concentration increased up to 60% when cells were left to stand in drug-free media for 3 h. These results indicated that the intracellular reducing conditions permitted the slow release of cisplatin (II) from the cisplatin (IV)-loaded nanoparticles. Similar results were obtained for the platination of mitochondrial DNA, which reached levels up to 17,400 ± 75 ng Pt/ mg DNA when cells were left in drug-free media for 3 h, proving that this organelle was also a target for the action of the released cisplatin (II). The time-dependent formation of Pt-DNA adducts could be correlated with the time-dependent decrease in cell viability. Such a decrease in cell viability was correlated with the induction of apoptosis as the main route of cell death. The formation of autophagosomes, although observed upon exposure in treated cells, does not seem to have played an important role as a means for cells to overcome nanoparticles’ toxicity. Thus, the designed nanosystem demonstrated high cellular penetration and the “in situ” production of the intracellularly active cisplatin (II), which is able to induce cell death, in a sustained manner.

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Section: Resultssupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Cellular Toxicity Mechanisms and the Role of Autophagy in Pt(IV) Prodrug-Loaded Ultrasmall Iron Oxide Nanoparticles Used for Enhanced Drug Delivery

et al. 2021

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“…Thus, platinum anti-cancer drugs have serious undesirable effects, including dose-limiting toxicity, especially nephrotoxicity, neurotoxicity, ototoxicity, and myelosuppression 14 , and long-term use of cisplatin causes serious damage to normal tissues 15 . Due to the considerable therapeutic effect of cisplatin and other first-line clinical platinum drugs on tumor tissues, various strategies have been employed to reduce the damage to normal tissues, such as liposome encapsulation 16 , 17 , drug delivery by nanomaterial carriers 18 , 19 , and bioconjunction targeting highly expressed protein moieties on tumors 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

Platinum-based drugs for cancer therapy and anti-tumor strategies

Zhang¹,

Xu²,

Gao³

et al. 2022

Theranostics

358

175

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Platinum-based drugs cisplatin, carboplatin, and oxaliplatin are widely used for chemotherapeutic eradication of cancer. However, the side effects of platinum drugs, such as lack of selectivity, high systemic toxicity, and drug resistance, seriously limit their clinical application. With advancements in nanotechnology and chemical synthesis, Pt-based anti-cancer drugs have made great progress in cancer therapy in recent years. Many strategies relied on the anti-cancer mechanism similar to cisplatin and achieved some success by modifying existing platinum drugs. Pt-based nanodrugs, such as platinum nanoclusters, have novel anti-cancer mechanisms and great potential in tumor-targeted therapy and have shown promising results in clinical application. In this review, we systematically explored the development of first-line platinum chemotherapy drugs in the clinic and their anti-cancer mechanisms. We also summarize the progress of Pt-based anti-cancer drug application in cancer therapy, emphasizing their modification to enhance the anti-tumor effect. Finally, we address challenges faced by platinum chemotherapy drugs, especially Pt nanocluster-based nanodrugs, in cancer treatment. The new platinum drugs and their targeted modifications undoubtedly provide a promising prospect for improving the current anti-cancer treatments.

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“…The final renal-to-hepatic-clearance ratio was approximately 2 (Supplementary Table S2). Organ biodistribution profiles showed liver uptake values as low as 3.7%ID following intravenous injection of 89 Zr-DFO-DOX-C 0 dots (Supplementary Table S3); these values are significantly lower than those reported for other nanocarrier-based drug delivery systems, for example, 64 Cu-labeled liposomes, with reported liver uptake values nearly 4-fold higher reported (40).…”

Section: Synthesis and Characterization Of Ph-sensitive Dfo-dox-c 0 Dotsmentioning

confidence: 78%

Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma

Aragon‐Sanabria

Aditya

Zhang

et al. 2022

Clinical Cancer Research

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Purpose: Despite dramatic growth in the number of small molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents which appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (< 8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C' dots), for the efficacious treatment of high-grade gliomas. Experimental Design: This work presents first-in-kind renally-clearable ultrasmall (< 8 nm) multimodal Cornell prime dots (or C' dots) with surface-conjugated doxorubicin via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models. Results: Optimal drug-per-particle ratios of as-developed nanoparticle-drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor-driven genetically engineered mouse model, and an epidermal growth factor expressing patient-derived xenograft (EGFR PDX) model. Conclusions: Ultrasmall C' dot-drug conjugates showed great translational potential over doxorubicin for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.

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Ultrasmall iron oxide nanoparticles cisplatin (IV) prodrug nanoconjugate: ICP-MS based strategies to evaluate the formation and drug delivery capabilities in single cells

Cited by 40 publications

References 32 publications

Cellular Toxicity Mechanisms and the Role of Autophagy in Pt(IV) Prodrug-Loaded Ultrasmall Iron Oxide Nanoparticles Used for Enhanced Drug Delivery

Cellular Toxicity Mechanisms and the Role of Autophagy in Pt(IV) Prodrug-Loaded Ultrasmall Iron Oxide Nanoparticles Used for Enhanced Drug Delivery

Platinum-based drugs for cancer therapy and anti-tumor strategies

Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma

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