Effect of Shape, Size, and Aspect Ratio on Nanoparticle Penetration and Distribution inside Solid Tissues Using 3D Spheroid Models

Abstract

Efficient penetration and uniform distribution of nanoparticles (NPs) inside solid tissues and tumors is paramount to their therapeutic and diagnostic success. While many studies have reported the effect of NP size and charge on intratissue distribution, role of shape, and aspect ratio on NP transport inside solid tissues remain unclear. Here experimental and theoretical studies are reported on how nanoscale geometry of Jet and Flash Imprint Lithography-fabricated, polyethylene-glycol-based anionic nanohydrogels affect their penetration and distribution inside 3D spheroids, a model representing the intervascular region of solid, tumor-like tissues. Unexpectedly, low aspect ratio cylindrical NPs (H/D ≈0.3; disk-like particles, 100 nm height, and 325 nm diameter) show maximal intratissue delivery (>50% increase in total cargo delivered) and more uniform penetration compared to nanorods or smaller NPs of the same shape. This is in contrast to spherical NPs where smaller NP size resulted in deeper, more uniform penetration. Our results provide fundamental new knowledge on NP transport inside solid tissues and further establish shape and aspect ratio as important design parameters in developing more efficient, better penetrating, nanocarriers for drug, or contrast-agent delivery.

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

“…Targeted small nanoconstructs with an elongated shape have the ability for deep tissue penetration due to hydrodynamic considerations 15,17 and are, therefore, highly promising types of nanodrugs. Our mini nanodrug consists of PMLA, attached to several HER2-specific AONs, 4 several 12-mer mimetic peptides that specifically target the HER2 receptor, 6–8 and a number of trileucine residues that manage the escape into the cytoplasm after endosome uptake into the recipient cell.…”

Multicellular Tumor Spheroids (MCTS) as a 3D In Vitro Evaluation Tool of Nanoparticles

“…The nanoparticles with diameters or length in the range of 200–800 nm were analyzed toward their ability to penetrate into MCTS. This study is one of the few known investigations into the effect of shape on diffusion …”

“…In one of the few studies, discs and cuboids, all well above 100 nm in size, prepared from PEG hydrogel, were compared showing faster penetration of disk structures. [67a] Comparison of Au nanoparticles (10, 30 , 50, and 70 nm) with nanorods of diameters of 10 and 25 nm and aspect ratios of around 3 and 5 revealed a significantly reduced uptake of rods into spheroids and a much slower movement into the center of MCTS . Block copolymers, prepared from fructose containing glycopolymers and PMMA, self‐assembled into small micelles, cylindrical micelles, and vesicles revealed that the small micelles could penetrated the MCTS very efficiently, followed by the cylindrical micelles and then the vesicles .…”

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

“…20 For example, 50 nm-sized lipid NPs showed a considerably deeper penetration and homogeneous distribution as compared to 120 nm-sized ones. 76 NPs .100 nm are too large to cross ECM interstitial spaces in spheroid 73,77 and are confined to the outer layers as demonstrated with gelatin NPs (210 nm) that only penetrated ~40 µm deep. 20 Micelles are generally smaller than liposomes and penetrate deeply and …”

“…For example, experimental findings showed that decreasing the aspect ratio from 0.45 to 0.30 improved NP accumulation and produced homogeneous penetration into spheroids. 77 Short nanorods (400 nm in length) accumulate more rapidly and are better internalized into spheroids as compared to long nanorods (,2,000 nm in length). 84 In addition, nanorods compared to nanospheres seem to diffuse more rapidly in spheroids.…”