Multifunctional Dendrimer-Entrapped Gold Nanoparticles Conjugated with Doxorubicin for pH-Responsive Drug Delivery and Targeted Computed Tomography Imaging

Abstract

Novel theranostic nanocarriers exhibit a desirable potential to treat diseases based on their ability to achieve targeted therapy while allowing for real-time imaging of the disease site. Development of such theranostic platforms is still quite challenging. Herein, we present the construction of multifunctional dendrimer-based theranostic nanosystem to achieve cancer cell chemotherapy and computed tomography (CT) imaging with targeting specificity. Doxorubicin (DOX), a model anticancer drug, was first covalently linked onto the partially acetylated poly­(amidoamine) dendrimers of generation 5 (G5) prefunctionalized with folic acid (FA) through acid-sensitive cis-aconityl linkage to form G5·NHAc-FA-DOX conjugates, which were then entrapped with gold (Au) nanoparticles (NPs) to create dendrimer-entrapped Au NPs (Au DENPs). We demonstrate that the prepared DOX-Au DENPs possess an Au core size of 2.8 nm, have 9.0 DOX moieties conjugated onto each dendrimer, and are colloid stable under different conditions. The formed DOX-Au DENPs exhibit a pH-responsive release profile of DOX because of the cis-aconityl linkage, having a faster DOX release rate under a slightly acidic pH condition than under a physiological pH. Importantly, because of the coexistence of targeting ligand FA and Au core NPs as a CT imaging agent, the multifunctional DOX-loaded Au DENPs afford specific chemotherapy and CT imaging of FA receptor-overexpressing cancer cells. The constructed DOX-conjugated Au DENPs hold a promising potential to be utilized for simultaneous chemotherapy and CT imaging of various types of cancer cells.

Polyethylenimine-Based Theranostic Nanoplatform for Glioma-Targeting Single-Photon Emission Computed Tomography Imaging and Anticancer Drug Delivery

“…The PEI surface amines are easily modi ed with PEG for PEGylation, which has been used as an effective strategy to overcome the systemic clearance and improve the pharmacokinetic properties [45,47]. In our previous studies, PEGylated PEI was developed as multifunctional templates to entrap gold NPs, label radionuclides, or load drugs for tumor imaging and treatment [48][49][50]. These PEI-based NPs could also be modi ed with targeting ligands for different tumors, for example, folic acid for cervical carcinoma and arginine-glycine-aspartic acid peptide for hepatic carcinoma [45,50].…”

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“…In 2018, Zhang and coworkers have reported the development of pH-sensitive multifunctional DOX-conjugated PAMAM dendrimers as a unique platform for targeted cancer chemotherapy [68]. Some other investigators have presented the construction of pH-responsive multifunctional dendrimer-based theranostic nanosystem (in which Gold nanoparticles conjugated with DOX were entrapped in dendrimer) to be utilized for simultaneous chemotherapy and computed tomography (CT) imaging of various types of cancer cells [69]. Dendritic polyester system based on monomers 2,2-bis (hydroxymethyl) propanoic acid attached to DOX or hydroxyl-terminated generation 4 PAMAM in conjugation with PTX through a union with succinic acid have shown great anticancer activity against ovarian cancer cells [65].…”

How can molecular micro-CT imaging revolutionize drug discovery?

“…Iodine-based CT contrast agents can be conjugated to various biomolecules, but it is very hard for such conjugates to be detected because of low sensitivity of conventional CT scanners. Therefore, in addition to the micro-CT imaging technique development, there exists an essential need to develop some new multifunctional complexes containing the new drug which is under investigation, CT contrast agent, and targeting/ biomarker ligand [9][10][11]. By the emergence of nanotechnology, development of such multifunctional complexes has been rapidly grown.…”

“…Nanoparticles made of high Z materials (such as gold, bismuth, barium, and tungsten) are the main components of theranostic nanoparticles which can be used as the CT scan contrast agents [13]. Such nanoparticles can be easily entrapped into a nanocarrier to be accompanied by drugs or genes [9][10][11]. They can be also conjugated with various targeting agents [14].…”