Targeting Tumors with Small Molecule Peptides

Abstract

Chemotherapeutic treatment of cancers is a challenging endeavor, hindered by poor selectivity towards tumorous tissues over healthy ones. Preferentially delivering a given drug to tumor sites necessitates the use of targeting elements, of which there are a wide range in development. In this Review, we highlight recent examples of peptide-based targeting ligands that have been exploited to selectively deliver a chemotherapeutic payload to specific tumor-associated sites such as the vasculature, lymphatics, or cell surface. The advantages and limitations of such approaches will be discussed with a view to potential future development. Additionally, we will also examine how peptide-based ligands can be used diagnostically in the detection and characterization of cancers through their incorporation into imaging agents.

Fig. (1).

Schematic illustration of targeting strategies in drug delivery. Passive targeting is based simply on extravasation of the drug or drug carrier through the leaky vasculature of the tumor. Active targeting is based on the binding of drug or carrier-conjugated ligand to its corresponding receptor on either the tumor endothelial cells (vasculature targeting) or tumor cell surface (tumor targeting).

Fig. (2).

Examples of tumor vasculature targeting peptides. (a) A Peptide-C based therapeutic that targets melanoma and inhibits angiogenesis through the conjugated anti-angiogenic peptide. (b) A shortened peptide mimic of a larger SPARC peptide that has tumor-homing properties. (c) LyP-1, a peptide that can be utilized to target a tumor’s lymphatic vasculature. (d) iRGD, a tumor penetrating peptide.

Fig. (3).

Examples of tumor-homing peptides and peptide-drug conjugates. (a) AEZS-108, in which the chemotherapeutic doxorubicin is conjugated to a modified LHRH peptide for the treatment of castration-resistant prostate cancer. (b) Conjugation of the anti-apoptotic α-TOS to the HER2-targeting peptide, LTVSPWY. (c) Octreotide and (d) lanreotide, two somatostatin analogues developed as both anti-tumor agents and targeting moieties).

Fig. (4).

Examples of peptide-drug conjugates that are used to target brain tumors. (a) Beliveau’s PTX-conjugated Angiopep-2 therapeutic, ANG1005. (b) c[RGDfK]-modified paclitaxel that is loaded into transferrin-bearing micelles for targeting of gliomas.

Fig. (5).

Examples of nanoimaging agents that utilize peptides in their design. (a) A dual-modality imaging agent developed by Chen et al., possessing an iron oxide nanoparticle core for MRI imaging and conjugated ⁶⁴Cu chelating DOTA groups for PET imaging. RGD peptide ligands target tumors displaying α_vβ₃ integrins. (b) Decay-corrected whole body coronal PET images of nude mouse bearing human U87MG tumor at 1, 4, and 21 h after injection of 3.7 MBq of the ⁶⁴Cu-containing imaging agent. These images show that it can accumulate in the tumor xenograft (white arrows), with uptake by the liver also indicated. (c) A quantum dot (QD) based fluorescence imaging agent, QD705-RGD, developed by Chen et al. This agent consists of a CdTe/ZnS with a PEG-polymer coating. The surface was decorated with cyclic-RGD ligands to enable targeting of α_vβ₃ integrins. (d) In vivo NIR fluorescence image of U87MG tumor-bearing mice 6 h after treatment with 200 pmol of QD705-RGD (left) and QD705 (right), showing how the RGD ligand allows accumulation in the tumor relative to a control QD imaging agent. Prominent uptake was also seen in the liver, bone marrow and lymph nodes. (e) An example of Pomper’s urea-based PSMA-targeting ligand with an 18F radiolabel. Preferential uptake is seen in a PSMA+ (PIP) tumor, but not a PSMA− (flu) tumor via PET imaging. (f) Schematic illustration of Cui’s nanobeacon (NB) concept. In the assembled state, the cleavable linker (GFLG) is inaccessible to the Cathepsin B protease and remains intact. Upon breakdown of the nanostructure, triggered by either dilution or a change in pH, the linker becomes accessible and cleavage occurs. The separation of the 5-FAM fluorophore from the BHQ-1 quencher results in a measurable signal that can be used to probe the activity of the protease. (g) Fluorescence images of MCF-7 human breast cancer cells incubated with NBs after 0 h (top) and 1.5 h (bottom). The cell nuclei were stained with the blue dye Hoechst 33342. (Images in (a) and (b) were adapted from ref. [220], (c)-(d) were adapted from ref. [225], (e) from ref. [226], and (f)-(g) were adapted from ref. [242]).