Progress in aptamer-mediated drug delivery vehicles for cancer targeting and its implications in addressing chemotherapeutic challenges

Abstract

Aptamers are novel oligonucleotides with flexible three-dimensional configurations that recognize and bind to their cognate targets, including tumor surface receptors, in a high-affinity and highly specific manner. Because of their unique intrinsic properties, a variety of aptamer-mediated nanovehicles have been developed to directionally transport anti-cancer drugs to tumor sites to minimize systemic cytotoxicity and to enhance permeation by these tumoricidal agents. Despite advances in the selection and synthesis of aptamers and in the conjugation and self-assembly of nanotechnologies, current chemotherapy and drug delivery systems face great challenges. These challenges are due to the limitations of aptamers and vehicles and because of complicated tumor mechanisms, including heterogeneity, anti-cancer drug resistance, and hypoxia-induced aberrances. In this review, we will summarize current approaches utilizing tumor surface hallmarks and aptamers and their roles and mechanisms in therapeutic nanovehicles targeting tumors. Delivery forms include nanoparticles, nanotubes, nanogels, aptamer-drug conjugates, and novel molecular trains. Moreover, the obstacles posed by the aforementioned issues will be highlighted, and possible solutions will be acknowledged. Furthermore, future perspectives will be presented, including cutting-edge integration with RNA interference nanotechnology and personalized chemotherapy, which will facilitate innovative approaches to aptamer-based therapeutics.

Keywords: aptamer; biomarker; chemotherapy; drug delivery; nanomedicine..

Figure 1

A conformational and interactional overview of aptamers and their receptors. (A) The sequential conformation (left) and secondary structure (right) of the commercialized aptamer product Macugen. (B) Schematic illustrations (left) and molecular models (right) of the quadruplex DNA for the aptamer AS1411. (C) The overall structure of the RNA aptamer C13 and its receptor, G protein-coupled receptor kinase 2 (GRK2). C13 positions an adenine nucleotide in the ATP-binding pocket of GRK2 (shown as yellow and burgundy ribbons), which stabilizes GRK2 in a unique and remodeled conformation. The terminal stem of the aptamer indirectly contributes to its affinity. Adapted from , .

Figure 2

A schematic illustration of novel forms of advanced AMNVs and their tumoricidal response in vitro and in vivo. (A) Lipid-polymer hybrid NPs combining the positive attributes of both liposomes and polymeric NPs and comprising a hydrophobic polymeric core (PLGA, drug and fluorescent dye) and a lipid layer conjugated to aptamers. (B) Self-assembled hybrid nanoparticles for the targeted co-delivery of two different drugs to cancer cells. A lipid-PEG-aptamer loaded with Dox forms the hydrophilic shell, whereas PLGA encapsulating PTX forms the hydrophobic core. (C) A poly-aptamer-drug composition based on rolling-circle amplification that induces cooperative binding and increases the strength and frequency of interactions with target tumor cells. (D) Aptamer-tethered DNA nanotrains, self-assembled from short DNA building blocks upon initiation from a chimeric aptamer-tethered trigger probe, significantly improve the drug payload capacity and the anti-tumor efficacy. (E-G) Increased endocytosis, cisplatin-d (GpG) intrastrand cross-links and cytotoxicity to tumor cells were confirmed by confocal laser scanning microscopy using different fluorescent probes (NR dye, R-C18 antibody and tubulin marker, respectively). Left, non-targeted NPs; right, aptamer-functionalized NPs. (H) The biodistribution discrepancy between non-targeted (left) and Muc1-targeted (right) QD-Dox conjugates shows active tumor targeting by preferentially accumulating in subcutaneous ovarian tumors. Adapted from , , .

Figure 3

The role of the tumor niche in the origin and influence of tumor heterogeneity, hypoxic aberrancy and the tumor-stroma interactome. Tumorigenesis involves the co-evolution of tumor cells with the ECM and vascular endothelial, immune and stromal cells (adapted from 52). Various anti-tumor strategies can be used to develop advanced AMNVs to overcome current limitations in chemotherapy, such as chimerization, co-delivery with siRNA, and stroma-targeted nanomedicine, among others. Aptamer is abbreviated as apt in this figure. * CEM and Toledo are different hemopoietic cancer cell lines; **MDA-MB-231 and SK-BR-3 are different breast cancer cell lines.