A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy

Abstract

Abstract Background 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. 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. 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) 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. Conclusions The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy. Graphical Abstract

Keywords

• Tumor microenvironment-responsive
• Chemodynamic therapy (CDT)
• Tirapazamine (TPZ)
• Synergistic therapy
• PAMAM dendrimer