Glycosylated Nanoparticles for Cancer-Targeted Drug Delivery

Abstract

Nanoparticles (NPs) are novel platforms that can carry both cancer-targeting molecules and drugs to avoid severe side effects due to nonspecific drug delivery in standard chemotherapy treatments. Cancer cells are characterized by abnormal membranes, metabolic changes, the presence of lectin receptors, glucose transporters (GLUT) overexpression, and glycosylation of immune receptors of programmed death on cell surfaces. These characteristics have led to the development of several strategies for cancer therapy, including a large number of carbohydrate-modified NPs, which have become desirable for use in cell-selective drug delivery systems because they increase nanoparticle-cell interactions and uptake of carried drugs. Currently, the potential of NP glycosylation to enhance the safety and efficacy of carried therapeutic antitumor agents has been widely acknowledged, and much information is accumulating in this field. This review seeks to highlight recent advances in NP stabilization, toxicity reduction, and pharmacokinetic improvement and the promising potential of NP glycosylation from the perspective of molecular mechanisms described for drug delivery systems for cancer therapy. From preclinical proof-of-concept to demonstration of therapeutic value in the clinic, the challenges and opportunities presented by glycosylated NPs, with a focus on their applicability in the development of nanodrugs, are discussed in this review.

Keywords: cancer therapy; drug delivery; glycoconjugates; glycodendrimers; glycopolymers; glycosylated nanoparticles.

Figure 1

A graphical representation of Warburg effect in cancer and experimental demonstrations of the improvement of glycosylated drug delivery systems for target cancer therapy (A) Metabolic differences between normal and cancer cells. In the presence of O₂, normal cells metabolize glucose in pyruvate followed by oxidative phosphorylation in the mitochondria generating 36 ATP per glucose molecule. In the deficiency of O₂, pyruvate is transformed to lactate via anaerobic glycolysis generating 2 ATP per glucose molecule. In cancer cell, mutations in mtDNA, nDNA or absence of p53 gene, presence of oncogenes and ROS suppress oxidative phosphorylation and enhances lactate production via glycolysis even in the presence of O₂ (Warburg effect). (B) Glycosylated PAMAM dendrimers conjugated with methotrexate as a strategy for breast cancer target therapy. (C) Comparison of viability between MDA-MB-231 and HaCaT cell lines. Cells were exposed to OS-PAMAM-MTX-GLU and control treatments at the same concentration of free MTX and GLU was calculated in encapsulation assay for 4 h. Data represent mean ± SD (n = 16). Statistical analysis was performed by two-way ANOVA followed by post hoc Tukey’s multiple comparisons test. ***P < 0.001, *<0.02. (D) Confocal images of MDA-MB-231 cells incubated for 2 and 12 h with OS-PAMAM-FITC and OS-PAMAM-FITC-MTX-GLU. For each group, the images from left to right showed the fluorescence of FITC (green), Hoechst 33342 (blue), and PI (red) stains. Images were acquired at 63×. Data has been contributed and modified from Torres-Pérez (14).