Abstract
Gastric cancer (GC) remains a major cause of death worldwide mainly because of the late detection in advanced stage. Recently, we proposed CD44v6 as a relevant marker for early detection of GC, opening new avenues for GC-targeted theranostics. Here, we designed a modular nanoscale system that selectively targets CD44v6-expressing GC cells by the site-oriented conjugation of a new-engineered CD44v6 half-antibody fragment to maleimide-modified polystyrene nanoparticles (PNPs) via an efficient bioorthogonal thiol-Michael addition click chemistry. PNPs with optimal particle size (200 nm) for crossing a developed biomimetic CD44v6-associated GC stromal model were further modified with a heterobifunctional maleimide crosslinker and click conjugated to the novel CD44v6 half-antibody fragment, obtained by chemical reduction of full antibody, without affecting its bioactivity. Collectively, our results confirmed the specific targeting ability of CD44v6-PNPs to CD44v6-expressing cells (1.65-fold higher than controls), highlighting the potential of CD44v6 half-antibody conjugated nanoparticles as promising and clinically relevant tools for the early diagnosis and therapy of GC. Additionally, the rational design of our nanoscale system may be explored for the development of several other nanotechnology-based disease-targeted approaches.
Highlights
Gastric cancer (GC) is the third leading cause of mortality worldwide, within the group of malignant diseases, accounting for 8.2% of total cancer-related deaths in 2018 [1]
Nanomaterials 2021, 11, 295 stomach, we have shown that CD44v6 is considerably de novo expressed in gastric premalignant and malignant lesions, while the normal gastric mucosa remains negative for this marker [14]
To create a modular system for site-specific immobilization of reduced half-antibody fragments, a combined chemical approach was followed: (1) first, carbodiimide chemistry was used to covalently bind a polyethylene glycol (PEG) linker, containing a maleimide moiety at one end and an amine group on the other (Mal-PEGNH2 ), to polystyrene nanoparticles (PNPs) surface carboxyl groups; (2) thiol-Michael addition click reaction was used to bind maleimides exposed at the surface of modified PNPs to free thiol groups of reduced half-antibody fragments [41]
Summary
Gastric cancer (GC) is the third leading cause of mortality worldwide, within the group of malignant diseases, accounting for 8.2% of total cancer-related deaths in 2018 [1]. Despite improvements in diagnosis and therapy, the prognosis of GC patients remains poor, mostly because of late detection at advanced stage, with an overall 5-year survival rate lower than. There is an unmet clinical need for the development of reliable, specific, and non-invasive screening methods for early detection and therapeutic treatment of GC. The field of nanomedicine has remarkably advanced, showing promise for the target-specific diagnosis and delivery of therapeutics to cancer [3,4,5]. The development of GC-targeted strategies is still at its infancy [6] due, in part, to the lack of specific biomarkers for GC cells [7,8].
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