Many tumor active targeting strategies, such as tumor microenvironment-triggered cell targeting and multivalent ligand approach for cell surface receptors, have been widely employed to construct nanocarriers as molecular imaging probes and therapeutic delivery vehicles for targeted tumor therapy. While the principle of each strategy has been well illustrated, due to the large macromolecular scaffold, most systems have difficulty in deep penetration of solid tumors, resulting in low tumor-targeting specificity and sensitivity. To overcome this problem, herein we develop a new family of tumor microenvironment-responsive supramolecular peptides with the combination of both strategies to simultaneously improve tumor-targeting specificity and sensitivity. Specifically, we append a cationic domain to the C-terminus of the targeting ligand conjugated self-assembling monomer precursor (SAM-P) through a cleavable chemical linker. Under the physiological condition, the SAM-P is unassembled due to electrostatic repulsion and has good tissue penetrating ability. At the tumor site, SAM-P undergoes tumor-triggered cleavage to release the active form of self-assembling monomer capable of forming supramolecular nanostructures with multivalent display of targeting ligands. Biophysical characterization confirms the chemical and physical transformation of SAM-P from unimers or oligomers with low ligand valency to supramolecular assemblies with high ligand valency under a tumor-mimicking reductive microenvironment. The <i>in vitro</i> fluorescence assay shows the importance of supramolecular morphology in mediating ligand-receptor interactions and targeting sensitivity. Enhanced targeting specificity and sensitivity can be achieved via tumor-triggered supramolecular assembly and induced multivalent ligand presentation toward cell surface receptors, respectively. The results support this combined tumor microenvironment-induced cell targeting and multivalent ligand display approach, and have great potential for use as cell-specific molecular imaging and therapeutic agents with high sensitivity and specificity.

Combined tumor environment triggered self-assembling peptide nanofibers and inducible multivalent ligand display for cancer cell targeting with enhanced sensitivity and specificity

ACS Spring Meeting 2021

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