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

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

Nanosystems for chemodynamic based combination therapy: Strategies and recent advances

“…In addition, ultrasound also enhances the Cu-induced Fenton-like reaction during the sonodynamic process to generate more ROS to achieve sonodynamic/chemodynamic improved synergistic tumor therapy. This study also confirmed that the antitumor mechanism of synergistic chemodynamic and sonodynamic therapies are associated with the upregulation of oxidative phosphorylation and ROS generation (Zhang M. et al, 2022).…”

“…With the rapid expansion of chemistry and materials science, nanotechnology shows great potential to overcome the limitations of conventional tumor therapy, and nanosystems (or nanotherapeutics) are regarded as one of the most promising strategies for better tumor treatment ( Zhang P. et al, 2022 ). The recent reports have revealed that the combination therapy strategies with CDT nanosystems can optimize the therapy effects and minimize the toxicity and adverse effects of treatment ( He et al, 2021 ; Yang et al, 2021 ; Liu Y. et al, 2022 ; Hao et al, 2022 ).…”

Cu2+-Chelating Mesoporous Silica Nanoparticles for Synergistic Chemotherapy/Chemodynamic Therapy

“…Therefore, the production of •OH can be detected by measuring the change in the absorbance of MB [55,56]. After adding H 2 O 2 for 24 h, the MB solution did not fade, indicating that MB was stable at this concentration of H 2 O 2 [57]. As demonstrated in Figure 2c, at pH = 5, the color of an MB solution containing H 2 O 2 almost completely faded after adding CP/CQ@MSN−HtB/Cu 2+ NPs.…”

Enhanced postoperative cancer therapy by iron-based hydrogels

“…CDT is a new ROS-mediated cancer treatment method based on in situ Fenton reaction in tumor site [ 102 , 119 , 120 ]. In the CDT process, metal ions such as Cu [ 121 ], Fe [ 122 ], Mn [ 123 ], catalyzed excessive endogenous H 2 O 2 in tumor microenvironment (TME) by Fenton or Fenton-like reaction to generate highly toxic •OH [ 124 ], which can specifically cause the death of tumor cells.…”