A Tumor Microenvironment-Responsive Poly (Amidoamine) Dendrimer Nanoplatform For Synergistic Hypoxia-Sensitive Chemo/Chemodynamic Therapy

Tumor microenvironment (TME) is characterized by weak acidity,high concentration of hydrogen peroxide(H₂O₂),excessive glutathione(GSH),and hypoxia,which has become a new target for tumor specific therapy.In recent years,various TME-responsive cancer treatment strategies have been developed and shown unique advantages in tumor treatment,such as chemodynamic therapy(CDT),which utilizes catalytic ions to induce Fenton/Fenton-like reactions at tumor sites with endogenous H₂O₂,and hypoxic-sensitive chemotherapy.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(?)and then encapsulate hypoxia-sensitive drug tirapazamine(TPZ)by the formation of hydrophobic Cu(?)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy of tumors overexpressing sialic acid residues.The formed G5.NHAc-PEG-PBA@Cu(?)/TPZ(GPPCT)with good stability could be specifically accumulated at tumors,efficiently taken up by tumor cells overexpressing sialic acid residues,and release Cu(?)and TPZ quickly in weakly acidic tumor sites via p H-sensitive dissociation of Cu(?)/TPZ.In vitro experiments demonstrated that GPPCT nanoplatform could efficiently target murine breast cancer cells(4T1)overexpressing sialic acid residues on surface,and show a significantly enhanced inhibitory effect on hypoxic cells with enormous toxic ROS generated in tumor cells.This is mainly due to that TPZ could be activated in hypoxic cells to produce·OH and BTZ free radicals,and the depletion of GSH in tumors by the reduction of Cu(?)to Cu(I),which may efficiently react with endogenous H₂O₂ to generate·OH by Fenton-like reaction for CDT.In vivo experiments demonstrated that the GPPCT nanoplatform could accumulate at tumor sites,significantly inhibit tumor growth by the synergistic effect of hypoxic-enhanced chemotherapy and CDT,effectively induce the apoptosis of hypoxic cells in solid tumor and inhibit the invasion and metastasis of tumor to lung.In summary,the developed GPPCT nanoplatform is a safe and efficient multifunctional nanoplatform for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.