Size-Dependent Drug Loading, Gene Complexation, Cell Uptake, and Transfection of a Novel Dendron-Lipid Nanoparticle for Drug/Gene Co-delivery

Abstract

Dendron micelles have shown promising results as a multifunctional delivery system, owing to their unique molecular architecture. Herein, we have prepared a novel poly(amidoamine) (PAMAM) dendron-lipid hybrid nanoparticle (DLNP) as a nanocarrier for drug/gene co-delivery and examined how the dendron generation of DLNPs impacts their cargo-carrying capabilities. DLNPs, formed by a thin-layer hydration method, were internally loaded with chemo-drugs and externally complexed with plasmids. Compared to generation 2 dendron DLNP (D2LNPs), D3LNPs demonstrated a higher drug encapsulation efficiency (31% vs 87%) and better gene complexation (minimal N/P ratio of 20:1 vs 5:1 for complexation) due to their smaller micellar aggregation number and higher charge density, respectively. Furthermore, D3LNPs were able to avoid endocytosis and subsequent lysosomal degradation and demonstrated a higher cellular uptake than D2LNPs. As a result, D3LNPs exhibited significantly enhanced antitumor and gene transfection efficacy in comparison to D2LNPs. These findings provide design cues for engineering multifunctional dendron-based nanotherapeutic systems for effective combination cancer treatment.

Cytochalasin B Treatment and Osmotic Pressure Enhance the Production of Extracellular Vesicles (EVs) with Improved Drug Loading Capacity

“…We then examined the drug loading efficiencies of the produced EVs and investigated the correlation with the amount of intravesicular protein. Generation 7 (G7) polyamidoamine (PAMAM) dendrimers were employed as a model drug due to their high degree of chemical versatility for manipulating the surface charge density [ 45 , 46 , 47 , 48 ]. Three types of G7 dendrimers, having either positive (G7-NH 2 ), neutral (G7-Ac), or negative (G7-COOH) charges were prepared using our previously developed protocols.…”

Dendritic–Linear Copolymer and Dendron Lipid Nanoparticles for Drug and Gene Delivery

“…24 We have similarly observed that G3 PAMAM−lipid micelles with unsaturated C12 tails resulted in more efficient gene transfection than G2 PAMAM−lipid micelles. 27 In contrast, Iwashita et al reported decreased transfection efficiency of polyplexes with G3 PAMAM and a pair of unsaturated C18 lipid tails despite the G3 forming a more stable complex. 69 Harada et al reported that larger PAMAM dendrons impeded the efficiency of cellular uptake, but once inside the cell, larger dendrons were more efficient at lysosomal escape.…”

“…(b) G2 PAMAM dendron is grown from an alkyl chain in divergent synthesis . (c) G2 PAMAM dendron is synthesized by a divergent technique and then conjugated to a DOPE phospholipid by copper-mediated click chemistry …”

“…26 More recently, Nair et al described a similar dendron−lipid conjugate generated by copper-catalyzed click chemistry of DOPE to PAMAM dendrons prepared by divergent synthesis (Figure 1b). 27 Other reported dendron−lipid micelles include polyglycerol dendrons conjugated to C18 alkyne by click chemistry, 28 polyglycerol dendrons synthesized by a divergent method from oleoyl chloride, 29 and carbosilane dendrons synthesized by a divergent method from various fatty acids. 30…”

Branched, dendritic, and hyperbranched polymers in liquid biopsy device design

“…Dendrons, used as precursors, may be attached to various central structures to prepare hybrid and multifunctional materials. An example of a G3 PAMAM dendron with a functional group compatible with click chemistry is illustrated in Figure 3c (Nair et al, 2021).…”