Development of Surface Chemical Strategies for Synthesizing Redox‐Responsive Diatomite Nanoparticles as a Green Platform for On‐Demand Intracellular Release of an Antisense Peptide Nucleic Acid Anticancer Agent

Abstract

Redox‐responsive silica drug delivery systems are synthesized by aeco‐friendly diatomite source to achieve on‐demand release of peptide nucleic acid (PNA) in tumor reducing microenvironment, aiming to inhibit the immune checkpoint programmed cell death 1 receptor/programmed cell death receptor ligand 1 (PD‐1/PD‐L1) in cancer cells. The nanoparticles (NPs) are coated with polyethylene glycol chains as gatekeepers to improve their physicochemical properties and control drug release through the cleavable disulfide bonds (S–S) in a reductive environment. This study describes different chemical conditions to achieve the highest NPs’ surface functionalization yield, exploring both multistep and one‐pot chemical functionalization strategies. The best formulation is used for covalent PNA conjugation via the S–S bond reaching a loading degree of 306 ± 25 µg PNA mg−1DNPs. These systems are used for in vitro studies to evaluate the kinetic release, biocompatibility, cellular uptake, and activity on different cancer cells expressing high levels of PD‐L1. The obtained results prove the safety of the NPs up to 200 µg mL−1 and their advantage for controlling and enhancing the PNA intracellular release as well as antitumor activity. Moreover, the downregulation of PD‐L1 observed only with MDA‐MB‐231 cancer cells paves the way for targeted immunotherapy.

Recent advances of silicate materials for wastewater treatment: a review

“…Various sources of silicon are used in the production of silicates, such as organic silicon, kaolin, and molecular sieves. Among these, diatomite stands out for its safety, cost-effectiveness, and environmentally friendly attributes, effectively addressing the limitations arising from the synthesis of composites [142]. Up to now, the use of diatomite as a raw material has led to the creation of various types of silicates [143,144].…”

Diatom-Based Nanomedicine for Colorectal Cancer Treatment: New Approaches for Old Challenges

“…Unfortunately, PNAs show limited tissue accessibility, low water solubility, and an unfavorable pharmacokinetic profile, hindering their translation into clinics [ 103 ]. Terracciano et al recently reported redox-responsive DNPs loaded with an anti-PD-L1 PNA for enhanced uptake in cancer cells and efficient protein downregulation [ 59 ] ( Table 1 ). The PNA was bound to polyethylene glycol (PEG)-modified DNPs via a disulfide bond with a loading efficiency of 31% and released after bond reduction by glutathione in cancer cells.…”

“…Due to the excess of glutathione in the tumor (2–20 mM) compared to normal tissues, the strategy shown by Terracciano et al promoted PNA release in malignant cells with higher efficiency than in healthy samples, reducing off-target protein downregulation and toxicity. Moreover, DNPs improved the uptake of PNA in A549 cells already after 6 h of incubation ( Figure 6 a), yielding an internalization four-fold higher than the free PNA [ 59 ]. Managò et al used Raman spectroscopy to determine the kinetics of internalization and localization of siRNA-loaded DNPs with an average diameter of 450 nm targeting cancer cells [ 104 ].…”

Exploiting the interaction between halloysite and charged PNAs for their controlled release

“…14 However, despite the remarkable potentialities possessed by PNAs, their poor water solubility, low uptake by eukaryotic cells, and rapid renal clearance have so far prevented the application of PNAs in the biomedical field. To overcome these limitations several strategies have been considered 15 even though the cellular uptake remains an unsolved issue and there are currently no drugs available based on PNA, even though a recent publication mentions one PNA drug in clinical trials, and others in development. 16 Recently, some of us reported the covalent linkage of PNA tetramers, chosen as a model, to HNTs to develop nanomaterials for intracellular PNA delivery.…”