Efficient Gene Therapy of Pancreatic Cancer via a Peptide Nucleic Acid (PNA)‐Loaded Layered Double Hydroxides (LDH) Nanoplatform

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant tumors with extremely poor prognosis due to the later stage diagnosis when surgical resection is no longer applicable. Alternatively, the traditional gene therapy which drives pancreatic cancer cells into an inactive state and inhibiting the proliferation and metastasis, presents potentials to safely inhibit pancreatic cancer progression, but unfortunately has received limited success to date. Here, an efficient gene therapy of pancreatic cancer is shown via a peptide nucleic acid (PNA)‐loaded layered double hydroxides (LDHs) nanoplatform. Compared with the traditional DNA‐ or RNA‐based gene therapies, the gene therapy using PNA features great advantages in recognizing and hybridizing with the target mutant sequences to form PNA–DNA hybrids with significantly enhanced stability due to the absence of electrostatic repulsion, and the constrained flexibility of the polyamide backbone. Moreover, ultrasmall LDHs are engineered to load PNA and the obtained PNA‐loaded LDH platform (LDHs/PNA) is capable of efficiently and selectively targeting the intranuclear mutant sequences thanks to the proton sponge effect. Treatments with LDHs/PNA demonstrate markedly inhibited growth of pancreatic cancer xenografts via a cancer cell proliferation suppression mechanism. The results demonstrate the great potentials of LDHs/PNA as a highly promising gene therapy agent for PDAC.

Peptide nucleic acids and their role in gene regulation and editing

“…Therefore, specifically silencing this mutated gene can potentially serve as a treatment strategy for pancreatic cancer. [ 47 ] Yu et al . reported a short PNA of 13 base pairs targeting the mutated KRAS G12D sequence loaded into a layered double hydroxides (LDHs) nanoplatform.…”

“…The PNA caused downregulation of the mutant oncogene and markedly inhibited tumor growth in PANC‐1 xenografted tumor‐bearing mice. [ 47 ] In a very similar approach, Lu et al . designed short antisense PNAs mediated by anthrax that targeted gene dependencies of cancer cells that resulted in decreased cell viability of the cancer cells.…”

“…Several more novel nanoplatforms such as lipid bicelles and LDHs have been reported in the recent past. [ 47,98 ] It is therefore evident that an impressive array of delivery mechanisms has been developed for the delivery of PNA into biological systems. While these delivery methods and related recent findings will not be discussed in detail in this review, the readers can refer to comprehensive overviews of these PNA delivery mechanisms elsewhere.…”

Multifunctional Delivery Systems for Peptide Nucleic Acids

“…In addition to silica-and silicon-based carriers, other nanostructured inorganic materials have been used for PNA delivery. In a recent work, 2D Mg-Al layered double hydroxides (LDHs) were used in combination with a PNA targeting the KRAS G12D mutated gene, and the inhibition of pancreatic cancer was evaluated in cells and in xenografted mice [195]. This work is interesting since the ability of PNA to discriminate between mutated and wild type DNA was exploited.…”

“…tated gene, and the inhibition of pancreatic cancer was evaluated in cells and in xenografted mice [195]. This work is interesting since the ability of PNA to discriminate between mutated and wild type DNA was exploited.…”