Aptamer-Functionalized Drug Nanocarrier Improves Hepatocellular Carcinoma toward Normal by Targeting Neoplastic Hepatocytes

Abstract

Site-specific delivery of chemotherapeutics specifically to neoplastic hepatocytes without affecting normal hepatocytes should be a focus for potential therapeutic management of hepatocellular carcinoma (HCC). The aptamer TLS 9a with phosphorothioate backbone modifications (L5) has not been explored so far for preferential delivery of therapeutics in neoplastic hepatocytes to induce apoptosis. Thus, the objective of the present investigation was to compare the therapeutic potential of L5-functionalized drug nanocarrier (PTX-NPL5) with those of the other experimental drug nanocarriers functionalized by previously reported HCC cell-targeting aptamers and non-aptamer ligands, such as galactosamine and apotransferrin. A myriad of well-defined investigations such as cell cycle analysis, TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) assay, and studies related to apoptosis, histopathology, and immunoblotting substantiated that PTX-NPL5 had the highest potency among the different ligand-attached experimental formulations in inducing selective apoptosis in neoplastic hepatocytes via a mitochondrial-dependent apoptotic pathway. PTX-NPL5 did not produce any notable toxic effects in healthy hepatocytes, thus unveiling a new and a safer option in targeted therapy for HCC. Molecular modeling study identified two cell-surface biomarker proteins (tumor-associated glycoprotein 72 and heat shock protein 70 [HSP70]) responsible for ligand-receptor interaction of L5 and preferential internalization of PTX-NPL5 via clathrin-mediated endocytosis in neoplastic hepatocytes. The potential of PTX-NPL5 has provided enough impetus for its rapid translation from the pre-clinical to clinical domain to establish itself as a targeted therapeutic to significantly prolong survival in HCC.

Plant-Based Antidiabetic Nanoformulations: The Emerging Paradigm for Effective Therapy

“…Fabrication of nanocarriers can also reduce the dose of drug and frequency of administration. Finally, fabricated nanoformulations can reduce the risk of toxic manifestations [1,188]. Thus, suitably designed nanoformulations of hypoglycaemic agents may offer improved therapeutic management of diabetes in the near future.…”

Mapping the gaps in chemical analysis for the characterisation of aptamer-target interactions

“…In the last 25 years, the number of publications dealing with aptamers and their applications has increased exponentially as shown in Figure 1. Nowadays aptamers are largely applied in therapeutics [6,9], diagnostics [10], drug delivery [11,12] and in sensing devices as biorecognition elements [13][14][15]. There were also developments in the selection process for aptamers and multiple variations exist, such as FluMag SELEX [16] which is nowadays the most commonly used one, capture-SELEX [17] developed specifically for small molecules and graphene oxide SELEX [18] that does not require immobilization of aptamer, or target, in contrast to other SELEX approaches.…”

Chemical conjugation of nucleic acid aptamers and synthetic polymers

“…Following these pioneer works of the Langer group, EDC-mediated amidation has been used in several other studies to surface-decorate PLGA-and PLGA-b-PEG-based nanoparticles prepared by the single/multiple emulsion-solvent evaporation method. [35][36][37][38][39][40][41][42][43] These nanoparticles have a hydrophobic core, which can be utilized for the delivery of poorly soluble molecules, and a surface hydrophilic layer which enables excellent aqueous solubility while providing a moiety for further conjugation to ligands, including aptamers. Recently, a PLGA-based layer-by-layer multifunctional aptamer-drug carrier system was developed by Danquah and coworkers using a double emulsion technique.…”