Abstract
BackgroundChemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy.ResultsIn 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) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity.ConclusionsThe targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.Graphical
Highlights
Tumor microenvironment (TME) is characterized by weak acidity, high concentration of hydrogen peroxide (H2O2), excessive glutathione (GSH), and hypoxia [1,2,3]
Cu(II) was complexed into the dendrimers by the tertiary amine groups, and TPZ molecules were loaded via the formation of hydrophobic Cu(II)/TPZ nanocomplexes to yield generation 5 (G5).NHAc-Polyethylene glycol (PEG)-Phenylboronic acid (PBA)@Cu(II)/TPZ (GPPCT) and G5.NHAc-mPEG@Cu(II)/TPZ (GmPCT)
The tumor weight of GPPCT group was the lowest. All these results clearly demonstrated the outstanding in vivo antitumor effect of targeted GPPCT nanoplatforms could effectively inhibit the growth of sialic acid overexpressed 4T1 tumors as a result of the synergistic therapeutic effect of hypoxia-enhanced chemotherapy and chemodynamic therapy (CDT)
Summary
Tumor microenvironment (TME) is characterized by weak acidity, high concentration of hydrogen peroxide (H2O2), excessive glutathione (GSH), and hypoxia [1,2,3]. In a typical CDT, transition metal ions, such as Fe(II) [16, 17], Cu(I) [11,12,13] and Mn(II) [18], are introduced to tumor sites, and highly toxic hydroxyl radicals (·OH) are generated by catalyzing the excess endogenous H2O2 at TME via Fenton or Fenton-like reaction [2]. Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. The low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy
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