Multifunctional Core–Shell Glyconanoparticles for Galectin-3-Targeted, Trigger-Responsive Combination Chemotherapy

Abstract

Galectin-3 (gal-3) plays a crucial role in various cellular events associated to tumor metastasis and progression. In this direction, gal-3 binding core–shell glyconanoparticles based on citrus pectin (CP) have been designed for targeted, trigger-responsive combination drug delivery. Depolymerization via periodate oxidation in heterogeneous medium yielded low-molecular weight dialdehyde oligomers (CPDA) of CP with a gal-3 binding property (K d = 160.90 μM). CPDA-based core–shell nanoparticles prepared to enhance the gal-3 binding specificity via a multivalent ligand presentation have shown to reduce homotypic cellular aggregation, tumor cell binding with endothelial cells, and endothelial tube formation, the major steps involved in the progression of cancer. Immune-fluorescence and flow cytometric analysis confirmed significant reduction in gal-3 expression on MDA-MB 231 cancer cells upon incubation with nanoparticles. An on-demand tumor microenvironment-responsive release of drugs at low pH and high concentrations of glucose and glutathione prevailing in tumor milieu was achieved by introducing a cleavable Schiff’s base, a boronate ester, and disulfide linkages within the shell of the nanoparticles. Nanoparticles with encapsulated sulindac in the core and doxorubicin (DOX) in the shell demonstrated target specificity and enhanced internalization with synergistic cytotoxic effects with a 30-fold reduction in IC50 in DOX-resistant, triple-negative MDA-MB 231 breast cancer cells. Nanoparticles were radiolabeled with 131I radioisotopes with ≥80% efficiency while retaining its gal-3 binding property. Biodistribution studies of radiolabeled placebo nanoparticles and drug-loaded CPDA nanoparticles demonstrated proof of concept of gal-3 targeting seen as preferential accumulation in the gal-3-expressing tissues of the gastric tract. The CPDA core–shell nanoparticles are thus promising platforms for gal-3 targeting and inhibition of gal-3-mediated processes involved in cancer progression with a potential of radiolabeling for in vivo monitoring or delivering therapeutic doses of radiation and on-demand triggered, target-specific drug release.

Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives

“…For example, increased Gal-3 levels are often detected in cancer patients’ blood, indicating that circulating Gal contributes to microenvironment reprogramming during cancer progression [ 75 , 138 ]. Circulating Gal-3 interacts with endothelial cells, which induce cytokine production that promotes cancer progression [ 139 , 140 ]. Colomb et al showed that Gal-3 interacts with CD146 on endothelial cells through affinity purification assays, which leads to AKT signaling activation and IL-6 and G-CSF secretion to promote cancer progression [ 141 ].…”

Galectin-3, Possible Role in Pathogenesis of Periodontal Diseases and Potential Therapeutic Target

“…Recently, Gal-3 binding core-shell glyconanoparticles based on citrus pectin, with Gal-3 inhibition properties, have been designed for targeted and combination drug delivery (Balakrishnan et al, 2020). These nanoparticles in vivo preferentialy accumulate in the Gal-3-expressing tissues of the gastrointestinal tract of mice suggesting their potential for targetspecific release of drug used in combination with glyconanoparticles based on citrus pectin and for specific Gal-3 targeting and inhibition of Gal-3-mediated processes (Balakrishnan et al, 2020).…”

Mechanochemical Drug Conjugation via pH-Responsive Imine Linkage for Polyether Prodrug Micelles

“…For that purpose, pH-responsive polymeric systems are particularly appealing to selectively release therapeutics by exploiting the various pH gradients that exist in specific cellular compartments. − The application of these polymers can further be expanded to other biological applications, including tumor-targeted delivery of drugs, intracellular delivery of nucleic acids or proteins, treatment of inflammatory diseases, and oral administration. , For example, imines, hydrazides, hydrazones, orthoesters, and acetal linkages degrade selectively in response to pH changes. , Among them, the imine linkage is of particular interest owing to its sensitivity under different acidic conditions, facilitating its widespread utility as a stimuli-responsive linkage. , As a notable example, Xu and co-workers conjugated doxorubicin to polymers through imine bond and demonstrated its pH-controlled drug release in acidic environments . In addition, Banerjee and co-workers developed pH-responsive glyconanoparticles conjugated to drugs through imine linkages …”

“…17 developed pH-responsive glyconanoparticles conjugated to drugs through imine linkages. 18 Despite active investigations into the prodrug approach with various carriers and therapeutic agents, the difference in solubility between each component can raise significant issues for effective conjugation. 19,20 On the other hand, mechanochemistry offers an alternative means to overcome this solubility limitation by alleviating the need for solvents.…”