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Tunable Design of Gold(III)–Doxorubicin Complex–PEGylated Nanocarrier. The Golden Doxorubicin for Oncological Applications

Author:
Moustaoui, Hanane, Movia, Dania, Dupont, Nathalie, Bouchemal, Nadia, Casale, Sandra, Djaker, Nadia, Savarin, Philippe, Prina-Mello, Adriele, de la Chapelle, Marc Lamy, Spadavecchia, Jolanda
Source:
ACS Applied Materials & Interfaces 2016 v.8 no.31 pp. 19946-19957
ISSN:
1944-8252
Subject:
Raman spectroscopy, doxorubicin, drug therapy, gold, humans, in vitro studies, ions, nanocarriers, nanogold, nanoparticles, neoplasm cells, nuclear magnetic resonance spectroscopy, pH, pancreatic neoplasms, polyclonal antibodies
Abstract:
To date, the translation of Au (III) complexes into chemotherapeutic agents has been hindered by their low stability under physiological conditions, a crucial parameter in drug development. In this study, we report an innovative four-step synthesis of a stable Au (III)–doxorubicin (DOX) complex, acting as a key constitutive component of doxorubicin-loaded PEG-coated nanoparticles (DOX IN–PEG–AuNPs). For therapeutic purposes, such AuNPs were then functionalized with the anti-Kᵥ11.1 polyclonal antibody (pAb), which specifically recognizes the hERG1 channel that is overexpressed on the membrane of human pancreatic cancer cells. The nature of the interactions between DOX and Au (III) ions was probed by various analytical techniques (Raman spectroscopy, UV–vis, and ¹H NMR), which enabled studying the Au (III)–DOX interactions during AuNPs formation. The theoretical characterization of the vibrational bands and the electronic transitions of the Au (III)–DOX complex calculated through computational studies showed significant qualitative agreement with the experimental observations on AuNPs samples. Stability in physiological conditions and efficient drug loading (up to to 85 w/w %) were achieved, while drug release was strongly dependent on the structure of DOX IN–PEG–AuNPs and on the pH. Furthermore, the interactions among DOX, PEG, and Au (III) ions in DOX IN–PEG–AuNPs differed significantly from those found in polymer-modified AuNPs loaded with DOX by covalent linkage, referred to as DOX ON–PEG–AuNPs. In vitro experiments indeed demonstrated that such differences strongly influenced the therapeutic potential of AuNPs in pancreatic cancer treatment, with a significant increase of the DOX therapeutic index when complexed to Au (III) ions. Collectively, our study demonstrated that Au (III)–DOX complexes as building blocks of PEGylated AuNPs constitutes a promising approach to transform promising Au (III) complexes into real chemotherapeutic drugs for the treatment of pancreatic cancer.
Agid:
5383597