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.

High drug-loading nanomedicines: progress, current status, and prospects

“…With this strategy, Moustaoui et al reported another ICP I-type high drug-loading nanomedicine, PEG-Au(III)-Dox, in a recent work. 165 In this nanomedicine, Dox molecules and dicarboxylic PEG molecules were chelated with Au(III) ions from tetrachloroauric acid (HAuC l4 ). It was demonstrated that nanomedicine depolymerization and effective Dox release were achieved at pH 4, with stability attained at a diameter close to 20 nm in physiological pH.…”

“…This strategy is only applied to drugs possessing complexation ability, such as carboxylates and phosphonates, including daunorubicin [165][166][167] The particle size and pHresponsive point of nanomedicines are dependent on the complex combinations of host ligands, drug molecules, and center metal ions. Computational design and combinatorial chemistry can be utilized as primary screening to equip ICP I-type nanomedicines with ideal properties.…”

Synthesis and characterization of a multifunctional gold-doxorubicin nanoparticle system for pH triggered intracellular anticancer drug release

“…It has also been reported that the intracellular drug delivery site can be monitored using surface enhanced Raman scattering (SERS) due to the surface plasmon resonance properties of the AuNPs [16,17]. AuNPs are often modified with polymers such as poly(ethylene glycol) (PEG) to improve its stability without altering its associated biocompatibility but simultaneously improving its potential in applications in the biomedical field [18][19][20]. In general, the presence of the PEG polymer is known to enhance the stability of colloidal AuNPs by increasing the electrostatic repulsion between the nanoparticles [21].…”

Novel Synthesis and Characterization of Doxycycline‐Loaded Gold Nanoparticles: The Golden Doxycycline for Antibacterial Applications

“…A fast reduction in the time of gold ion, was observed when the reaction was performed at room temperature under basic conditions (NaOH). It is well established that amine and carbonyl groups can easily chelate and transfer electrons to gold ions (Au 3+ ), leading to the formation of Au 0 (nuclei)/Au‐amine complexes via simple amine‐carbonyl chemistry . Pending the reduction of gold ions (AuCl 4 − ) exploiting DOXY drives to a rise in the rate of reduction of the gold ions, which favors an enhanced nucleation rate with the formation of a gold grains .…”

“…However, the formulation in use has shown dramatic side effects as their low bioavailability, is responsible for delivery problems and consequently of systemic toxicity that limited their medical application . Recently, Spadavecchia and co‐workers have synthesized an original nanovector based on doxorubicin–gold complex, by a chelation reaction in which, the drug was complex with tetrachloauric acid (HAuCl 4 ) and polymer molecules before reduction to final nanovector (DOX IN‐AuNPs) . The same authors have also studied the mechanism of hybrid nanoparticles using doxorubicin capped onto gold nanoparticles with biocompatible polymers as capping agent (DOX ON‐AuNPs) in order to compare the different activity of both nanovectors, and their remarkable interest in therapeutic activity to in vitro model of pancreatic ductal adeno carcinoma …”