Active Targeting of Dendritic Polyglycerols for Diagnostic Cancer Imaging

Abstract

Active tumor targeting involves the decoration of nanomaterials (NMs) with oncotropic vector biomolecules that selectively recognize certain antigens on malignant cells or in the tumor microenvironment. This strategy can facilitate intracellular uptake of NM through specific interactions such as receptor‐mediated endocytosis and can lead to prolonged retention in the malignant tissues by preventing rapid efflux from the tumor. Here, the design of actively targeting, renally excretible bimodal dendritic polyglycerols (dPGs) for diagnostic cancer imaging is described. Single‐domain antibodies (sdAbs) specifically binding to the epidermal growth factor receptor (EGFR) are employed herein as targeting warheads owing to their small size and high affinity for their corresponding antigen. The dPGs equipped with EGFR‐targeting feature are compared head‐to‐head with their nontargeting counterparts in terms of interaction with EGFR‐overexpressing cells in vitro as well as accumulation at receptor‐positive tumors in vivo. Experimental results reveal a higher specificity and preferential tumor accumulation for the α‐EGFR dPGs, resulting from the introduction of active targeting capabilities on their backbone. These results highlight the potential for improving the tumor uptake properties of dPGs by strategic use of sdAb functionalization, which can ultimately prove useful to the development of ultrasmall NM with highly specific tumor accumulation.

Engineering precision nanoparticles for drug delivery

“…To further prevent non-specific distribution, many NP platforms have added targeting moieties to their surface to direct their delivery. Most targeting moieties — including antibodies 121 , glucose 122 , transferrin 34 , folate 123 , transporters 2 and integrin ligands 124 — use interactions with molecules on the target cell’s surface, such as ligand–receptor, enzyme–substrate or antibody–antigen-mediated interactions 73 . Thus, targeted NPs must be engineered with a targeting moiety density that allows for these cell surface interactions, making it important to understand the ratio of receptors to ligands and the number of interactions needed to overcome the initial energy barrier to NP uptake 2 , 76 .…”

“…Antibodies, carbohydrates and other ligands on the NP surface can induce specific and efficient NP uptake 124 . Examples of tumour cell targeting moieties include antibodies 121 , peptides 126 , integrin ligands 124 , glucose 122 , transferrin 34 , 215 and folic acid 123 (Fig. 5 ).…”

Challenges in the development of nanoparticle‐based imaging agents: Characterization and biology

“…Without active targeting, long circulating nanoparticles, such as liposomes, distribute exclusively by passive, EPR effect and remain close to the vasculature or within tumor macrophage instead of distributing throughout the tissue (Kirpotin et al, 2006). On the other hand, “smaller” nanoparticle formulations without active targeting have a tendency to wash in and out of the tissue (Pant et al, 2020). With regard to the delivery efficiency of nanoparticles, new data have suggested that the EPR effect is very poor at accumulating drug within tumor, even within preclinical models (Cheng, He, Riviere, Monteiro‐Riviere, & Lin, 2020; Wilhelm et al, 2016).…”

Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics

“…Additionally, 89 Zr-HER3 ( 23 ), 18 F-HER2 ( 24 ), and 68 Ga-NOTA-CD20 ( 25 ) nanobodies have demonstrated success in various tumor models. Pant et al ( 26 ) developed a novel implementation of anti-EGFR-nanobody-dendritic polyglycerols (dPGs), demonstrating enhanced accumulation in vivo . 99m Tc-EGFR ( 27 ), 99m Tc-EGFR-cartilage oligomeric matrix protein (COMP) ( 28 ), 99m Tc-dipeptidyl-peptidase-like protein 6 (DPP6) ( 29 ), 99m Tc-mesothelin ( 30 ), and 131 I-HER2 ( 31 ) nanobodies nanobody probes have also demonstrated high T/B ratios.…”