Enhanced selectivity, cellular uptake, and <i>in vitro</i> activity of an intrinsically fluorescent copper–tirapazamine nanocomplex for hypoxia targeted therapy in prostate cancer

Silva, Vera Lucia Domingues; Kaassis, Abdessamad Y. A.; Dehsorkhi, Ashkan; Koffi, Cédrik-Roland; Severic, Maja; Abdelhamid, Moustafa Salaheldin; Nyimanu, Duuamene; Morris, C J; Al-Jamal, Wafa' T

doi:10.1039/c9bm01905g

Cited by 17 publications

(24 citation statements)

References 45 publications

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“…S8a, and a signi cantly higher amount of TPZ were released at weak acidic than at physiological situation. The pH-sensitive release property of GPPCT should be attributed to the easier dissociation of Cu(II)/TPZ complex at a lower pH [12]. As a result, GPPCT nanoplatform may decrease the side effects by reducing drug release during body circulation, and release Cu(II) and TPZ quickly at weak acidic tumor sites for e cient CDT and chemotherapy.…”

Section: Resultsmentioning

confidence: 99%

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A Tumor Microenvironment-Responsive Poly(amidoamine) Dendrimer Nanoplatform for Hypoxia-Responsive Chemo/Chemodynamic Therapy

Hao

Gao

Fan

et al. 2021

Preprint

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Background: Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, since toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction at the tumor microenvironment (TME) with low pH and high endogenous hydrogen peroxide (H2O2). However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict its curative outcomes.Results: In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) with good stability could be specifically accumulated at tumors, efficiently taken up by tumor cells overexpressing sialic acid residues, and release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro and in vivo experiments using murine breast cancer cells (4T1) demonstrated that the GPPCT nanoplatform could efficiently generate toxic ·OH in tumor cells while simultaneously deplete GSH, effectively kill hypoxic tumor cells by activated TPZ radicals, reduce tumor metastasis, and show no significant systemic toxicity.Conclusions: The targeted GPPCT nanoplatform may be developed for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.

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Section: Resultsmentioning

confidence: 99%

“…In addition, normalization of TME may in turn improve tumor therapy outcome [4]. Thereby a large number of TME-responsive cancer treatment strategies have been developed in recent years, including chemodynamic therapy (CDT) [8][9][10] and hypoxic-sensitive chemotherapy [11,12].…”

Section: Introductionmentioning

confidence: 99%

A Tumor Microenvironment-Responsive Poly(amidoamine) Dendrimer Nanoplatform for Hypoxia-Responsive Chemo/Chemodynamic Therapy

Hao

Gao

Fan

et al. 2021

Preprint

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“…One of the most recent and revolutionary strategies that have been suggested to improve treatment response is nanoparticles containing combination of HIF-targeted drugs [ 98 , 99 ], anti-angiogenic agents [100] and/or hypoxia-activated prodrugs [ 2 , 101 , 102 ]. Considering most hypoxia-activated prodrugs have failed clinical trials, likely due to insufficient drug delivery, a recent in silico analysis attempted to evaluate the outcomes of lipidic nanoparticles containing both anti-angiogenic agents (AAs) and hypoxia-activated prodrugs (HAPs), in an attempt to improve HAPs delivery and efficiency.…”

Section: Hypoxia-targeted Combinatorial Therapy Via Nanoparticlesmentioning

confidence: 99%

Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer

Codony

Tavassoli

2021

Translational Oncology

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“…Their mechanism of action work by their enzymatic reduction to reactive oxygen species under hypoxic conditions, with capacity to re-oxidize in oxygenated environments. In pre-clinical and clinical settings, hypoxia activated prodrugs have shown promising efficacy in successfully attacking hypoxic cells of solid tumors (186)(187)(188). This approach has been more efficacious when combined with chemotherapy and radiotherapy (189,190), as well as anti-angiogenic therapies (191)(192)(193).…”

Section: Reversal Of Hypoxia As An Approach To Personalized Therapymentioning

confidence: 99%

Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer

et al. 2021

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Epithelial ovarian cancer is predominantly diagnosed at advanced stages which creates significant therapeutic challenges. As a result, the 5-year survival rate is low. Within ovarian cancer, significant tumor heterogeneity exists, and the tumor microenvironment is diverse. Tumor heterogeneity leads to diversity in therapy response within the tumor, which can lead to resistance or recurrence. Advancements in therapy development and tumor profiling have initiated a shift from a “one-size-fits-all” approach towards precision patient-based therapies. Here, we review aspects of ovarian tumor heterogeneity that facilitate tumorigenesis and contribute to treatment failure. These tumor characteristics should be considered when designing novel therapies or characterizing mechanisms of treatment resistance. Individual patients vary considerably in terms of age, fertility and contraceptive use which innately affects the endocrine milieu in the ovary. Similarly, individual tumors differ significantly in their immune profile, which can impact the efficacy of immunotherapies. Tumor size, presence of malignant ascites and vascular density further alters the tumor microenvironment, creating areas of significant hypoxia that is notorious for increasing tumorigenesis, resistance to standard of care therapies and promoting stemness and metastases. We further expand on strategies aimed at improving oxygenation status in tumors to dampen downstream effects of hypoxia and set the stage for better response to therapy.

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Enhanced selectivity, cellular uptake, and in vitro activity of an intrinsically fluorescent copper–tirapazamine nanocomplex for hypoxia targeted therapy in prostate cancer

Abstract: Cu(TPZ)2 complex as a promising hypoxia selective cytotoxin in prostate cancer.

Cited by 17 publications

References 45 publications

A Tumor Microenvironment-Responsive Poly(amidoamine) Dendrimer Nanoplatform for Hypoxia-Responsive Chemo/Chemodynamic Therapy

A Tumor Microenvironment-Responsive Poly(amidoamine) Dendrimer Nanoplatform for Hypoxia-Responsive Chemo/Chemodynamic Therapy

Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer

Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer

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