Abstract
To penetrate solid tumors, low molecular weight (Mw < 10 KDa) compounds have an edge over antibodies: their higher penetration because of their small size. Because of the dense stroma and high interstitial fluid pressure of solid tumors, the penetration of higher Mw compounds is unfavored and being small thus becomes an advantage. This review covers a wide range of peptidic ligands—linear, cyclic, macrocyclic and cyclotidic peptides—to target tumors: We describe the main tools to identify peptides experimentally, such as phage display, and the possible chemical modifications to enhance the properties of the identified peptides. We also review in silico identification of peptides and the most salient non-peptidic ligands in clinical stages. We later focus the attention on the current validated ligands available to target different tumor compartments: blood vessels, extracelullar matrix, and tumor associated macrophages. The clinical advances and failures of these ligands and their therapeutic conjugates will be discussed. We aim to present the reader with the state-of-the-art in targeting tumors, by using low Mw molecules, and the tools to identify new ligands.
Highlights
To penetrate solid tumors, low molecular weight (Mw < 10 KDa) compounds have an edge over antibodies: their higher penetration because of their small size
The applicability of the DAG peptide was demonstrated for Alzheimer’s disease, as we found that CTGF is overexpressed in early and late stages of the disease in mice and in humans [20]
By performing the phage selection on MatrigelTM, the authors were able to identify a peptide that binds to an extracellular matrix (ECM) target that is not associated with blood vessels or in the vicinity of the vasculature
Summary
Low Mw entities offer fundamental advantages over high Mw entities like antibodies or nanoparticles [1,2]. Many tumors like pancreatic and breast dramatically overexpress stromal components, mostly collagen and hyaluronic acid [3,4,5]. This represents a serious barrier that impedes the penetration of large molecules (such as antibodies), because of their lower diffusion coefficient and the high interstitial fluid pressure [6,7,8]. In designing mouse-based preclinical studies, the targeting ligand should be chosen based on the tumor type and a marker consensuated to be over-expressed in that cancer in mice and humans.
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