title: Tunable Design of Gold(III)-Doxorubicin Complex-PEGylated Nanocarrier. The Golden Doxorubicin for Oncological Applications.
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 (1)H 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.
authors.affiliation: CNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d'Agents Therapeutiques Université Paris 13 , Sorbonne Paris Cité, 93000 Bobigny, France.
authors.forename: Hanane
authors.initials: H
authors.lastname: Moustaoui
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Dania
authors.initials: D
authors.lastname: Movia
authors.affiliation: CNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d'Agents Therapeutiques Université Paris 13 , Sorbonne Paris Cité, 93000 Bobigny, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dupont
authors.affiliation: CNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d'Agents Therapeutiques Université Paris 13 , Sorbonne Paris Cité, 93000 Bobigny, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bouchemal
authors.affiliation: Sorbonne Universités, UPMC Univ Paris VI , Laboratoire de Réactivité de Surface, 4 place Jussieu, F-75005 Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Casale
authors.affiliation: CNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d'Agents Therapeutiques Université Paris 13 , Sorbonne Paris Cité, 93000 Bobigny, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Djaker
authors.affiliation: CNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d'Agents Therapeutiques Université Paris 13 , Sorbonne Paris Cité, 93000 Bobigny, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Savarin
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College Dublin , Dublin 2, Ireland.|AMBER Centre, CRANN Institute, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Adriele
authors.initials: A
authors.lastname: Prina-Mello
authors.affiliation: CNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d'Agents Therapeutiques Université Paris 13 , Sorbonne Paris Cité, 93000 Bobigny, France.
authors.forename: Marc Lamy
authors.initials: ML
authors.lastname: de la Chapelle
authors.affiliation: CNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d'Agents Therapeutiques Université Paris 13 , Sorbonne Paris Cité, 93000 Bobigny, France.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Spadavecchia
mesh_terms: D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D004317:Doxorubicin; D004337:Drug Carriers; D065546:Drug Liberation; D006046:Gold / Q000737:chemistry*; D006801:Humans; D049329:Nanostructures; D011092:Polyethylene Glycols
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011092:Polyethylene Glycols; D006046:Gold; D004317:Doxorubicin
keywords: 1H NMR; AuNPs; DFT; PDAC; Raman spectroscopy; gold−doxorubicin complex