Exploring Maleimide-Based Nanoparticle Surface Engineering to Control Cellular Interactions

Abstract

Nanoparticle cellular interactions are governed by nanoparticle surface chemistry and the surface display of functional (bio)molecules. To conjugate and display thiol-containing (bio)molecules on nanoparticle surfaces, reactions between thiols and functional maleimide groups are often exploited. However, current procedures for modifying nanoparticle surfaces with maleimide groups are complex and can result in nanoparticle aggregation. Here, we demonstrate a straightforward, fast (∼30 min), efficient, and robust one-step surface engineering protocol for modifying gold nanoparticles with functional maleimide groups. We designed a hetero-bifunctional poly(ethylene glycol)-based molecule that attaches efficiently to the gold nanoparticle surface in a single step via its orthopyridyl disulfide (OPSS) terminal end, leaving its maleimide functional group available for downstream reaction with thiols. Using this surface engineering approach, we fabricated gold nanoparticles with near neutral and positive surface charges, respectively. We demonstrate that nanoparticle cellular uptake efficiencies in model mouse breast cancer (4T1) cells, human breast cancer (MDA-MB-231) cells, and human umbilical vein endothelial (HUVEC) cells in tissue culture can be tuned by up to 3 orders of magnitude by adjusting nanoparticle surface chemistry. Our straightforward and efficient maleimide-based nanoparticle surface engineering protocol creates a platform technology for controlled covalent surface attachment of a variety of thiol-containing (bio)molecules to nanoparticles for rational design of nanomaterials with precise cellular interactions for widespread applications in bioanalysis and nanomedicine.

Development of HER2-Targeting-Ligand-Modified Albumin Nanoparticles Based on the SpyTag/SpyCatcher System for Photothermal Therapy

“…The ligation of SC-HER2Afb with HSA-ST-ICG NPs via the ST/SC reaction is more effective than those reported in previous studies with a sufficient amount of surface functionalization (60 μg/mg), a fast reaction rate (within 6 h), and high reaction efficiency (∼100%). − These results were confirmed by SDS-PAGE analyses in time- and concentration-dependent manners. Surface functionalization with HSA-ST-ICG NPs and SC-HER2Afb also has the added advantage of simplifying the production process as it does not require the removal of unreacted linkers because it does not use reactive linkers such as NHS and MAL.…”

Synthesis of Poly(Malic Acid) Derivatives End-Functionalized with Peptides and Preparation of Biocompatible Nanoparticles to Target Hepatoma Cells

“…As widely recognized, the thiol-maleimide reaction, also known as Michael addition, allows us to easily conjugate peptides with a thiol function at either their N- or C-terminal position to polymeric materials, lipids, nanoparticles, liposomes or biomolecules, presenting an accessible maleimide group [ 16 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Such Michael addition has been described to take place under mild conditions of pH and temperature, and to be conducted in aqueous and/or organic solutions [ 16 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Moreover, maleimide functions are also well-known to have a very strong affinity and specificity towards thiol groups.…”

“…Moreover, maleimide functions are also well-known to have a very strong affinity and specificity towards thiol groups. Therefore, Michael addition can be realized with (macro)molecules and/or nanoobjects without reacting with other functional groups such as amines and carboxylic acids [ 16 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

Strategies for Delivering Nanoparticles across Tumor Blood Vessels

“…A common method of accomplishing this is through the modification of the nanoparticle surfaces with molecular ligands that are specific to endocytic receptors, along with necessary intermediates, as mentioned with the transferrin, albumin, and folic acid conjugations. [ 95,118,119,145–147 ] Table 2 lists several common nanoparticle surface ligands, the receptors that these ligands target, and the pathways these ligands are internalized by cells.…”