Enhanced Cellular Uptake of Peptide-Targeted Nanoparticles through Increased Peptide Hydrophilicity and Optimized Ethylene Glycol Peptide-Linker Length

Abstract

Ligand-targeted nanoparticles are emerging drug delivery vehicles for cancer therapy. Here, we demonstrate that the cellular uptake of peptide-targeted liposomes and micelles can be significantly enhanced by increasing the hydrophilicity of the targeting peptide sequence while simultaneously optimizing the EG peptide-linker length. Two distinct disease models were analyzed, as the nanoparticles were functionalized with either VLA-4 or HER2 antagonistic peptides to target multiple myeloma or breast cancer cells, respectively. Our results demonstrated that including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake of targeted nanoparticles up to ∼80-fold using an EG6 peptide-linker in liposomes and ∼27-fold using an EG18 peptide-linker in micelles for the VLA-4/multiple myeloma system. Similar trends were also observed in the HER2/breast cancer system with the EG18 peptide-linker resulting in optimal uptake for both types of nanoparticles. Cellular uptake efficiency of these formulations was also confirmed under fluidic conditions mimicking physiological systems. Taken together, these results demonstrated the significance of using the right design elements to improve the cellular uptake of nanoparticles.

Protein Mimetic and Anticancer Properties of Monocyte-Targeting Peptide Amphiphile Micelles

“…The enhanced cytotoxicity of MCP-1 PAM could be attributed to increased cellular uptake of the nanoparticle compared to free peptide as reported in other systems. 64 …”

Optimizing Circulating Tumor Cells’ Capture Efficiency of Magnetic Nanogels by Transferrin Decoration

“…The synthesis of tPG diazide (N 3 -tPG-N 3 ) was performed by ring-opening polymerization of GME and EGE and subsequently followed by mesylation and diazidation of the polymer endings. The presence of the azide groups was confirmed by FT-IR due to the appearance of the signal characteristic of the azide group at 2100 cm To covalently attach the Tf to the MNGs, we chose a strategy that implied the use of a linker that guaranteed enough freedom to the protein when it was attached to the MNGs to interact with the cellular receptors [45,46]. We proposed heterobifunctional PEGs of different lengths as linkers and with azide and N-hydroxysuccinimide (NHS) as functional groups on the polymer endings.…”

“…[45,46] We proposed heterobifunctional PEGs of different lengths as linkers and with azide and N-hydroxysuccinimide (NHS) as functional groups on the polymer endings. NHS was used to conjugate the linker to the lysine residues of the Tf by amide bonding, whereas the azido groups were employed to couple by strain-promoted cycloaddition to the BCN moieties from the MNGs that were not involved in its formation.…”

Guiding Principles in The Design of Ligand-Targeted Nanomedicines

“…However, while PEG polymers have dominated surface passivation applications to date, their use has not escaped criticism. For example, ligands attached to surface-tethered PEGs will often conceal themselves in the PEG layer and thereby avoid interaction with their receptors [75,76]. Moreover, repeated administration of PEGylated NPs has been reported to cause kidney toxicity and elicit anti-PEG antibody production [77][78][79].…”