Hybrid Nanoparticle System Integrating Tumor-Derived Exosomes and Poly(amidoamine) Dendrimers: Implications for an Effective Gene Delivery Platform

Abstract

Nanoscale drug delivery systems for cancer treatment have demonstrated promising results in enhancing the selectivity of therapeutic agents while reducing their toxic side effects. However, several biological and physical barriers, such as the immunogenicity and undesirable biodistributions of such delivery systems, have hindered their fast translation. To address these issues, we have developed an exosome−dendrimer hybrid nanoparticle (NP) platform to combine the advantageous biological properties of natural exosomes and synthetic dendrimers into a single NP system. The novel hybrid NPs, consisting of exosomes derived from MCF7 cells and functionalized poly-(amidoamine) (PAMAM) dendrimers, were prepared using sonication and characterized in terms of loading efficiency, size, cytotoxicity, and cellular interactions. Our results indicate that the loading of dendrimers into exosomes is dependent on dendrimer size and charge. The hybrid NPs inherited the size (∼150 nm), surface charge (−10 mV), and surface protein markers (CD81 and CD63) of exosomes. Importantly, the hybrid NPs enhanced the cellular internalization of amine-terminated PAMAM dendrimers (p < 0.05) while exhibiting substantially lower cytotoxicity than the free positively charged dendrimers (113.3 vs 35.6% of cell viability at 500 nM, p < 0.05). These advantageous properties of hybrid NPs were leveraged for use as a gene delivery vehicle, resulting in enhanced oligonucleotide delivery (over 2-fold) to cancer cells, compared to dendrimers alone. Furthermore, the hybrid NPs effectively delivered small interfering RNA (siRNA) as well, downregulating programmed death-ligand 1 (PD-L1) expression significantly more (3.8-fold) than dendrimers alone (p < 0.05). Our results demonstrate that the individual characteristics of both exosomes and dendrimers can be integrated to generate a multifaceted NP platform, proposing a novel NP design strategy.

Polyurethane Nanoparticles as Versatile Tools in Nanomedicine: A Review

“…Surface modification endeavors to modify a material’s surface properties and functionality for a specific purpose without adversely influencing the bulk properties. − …”

Material and Design Toolkit for Drug Delivery: State of the Art, Trends, and Challenges

“…(D) Schematic representation of exosome-PAMAM dendrimer hybridization. Reproduced with permission from ref . Copyright 2022 American Chemical Society.…”

“…Exosomes can be utilized in combination with other NPs on a hybrid platform. In a study, exosomes combined with dendrimers to develop an improved nanoparticle that contains exosomes’ biological properties besides dendrimers’ specific properties . As presented in Figure d, the hybridization process was performed by sonicating functionalized PAMAM dendrimers and exosomes derived from MCF7 cells.…”

Cell internalization kinetics and surface charge accessibility of surface-modified PAMAM dendrimers

“…3 Over the years, PAMAM dendrimers have gained significant relevance as drugdelivery vehicles due to their biocompatibility, tuneable surface chemistry, and versatility to encapsulate and deliver various therapeutic agents. [4][5][6][7][8] In physiological conditions, PAMAM dendrimers have a polycationic structure due to the protonation of their terminal primary amines ( pK a ∼ 9). 9 This cationic structure is responsible for the charge-dependent cytotoxicity of PAMAM, as the positively charged groups interact with and disrupt the integrity of negatively charged cell membranes.…”

“…3 Over the years, PAMAM dendrimers have gained significant relevance as drug-delivery vehicles due to their biocompatibility, tuneable surface chemistry, and versatility to encapsulate and deliver various therapeutic agents. 4–8…”