Enhanced transfection of tumor cellsin vivousing “Smart” pH-sensitive TAT-modified pegylated liposomes

Abstract

Liposomes have been prepared loaded with DNA (plasmid encoding for the green fluorescent protein, GFP) and additionally modified with TATp and PEG, with PEG being attached to the liposome surface via both pH-sensitive hydrazone and non-pH-sensitive bonds. The pGFP-loaded liposomal preparations have been administered intratumorarly in tumor-bearing mice and the efficacy of tumor cell transfection was followed after 72 h. The administration of pGFP-TATpliposomes with non-pH-sensitive PEG coating has resulted in only minimal transfection of tumor cells because of steric hindrances for the liposome-to-cell interaction created by the PEG coat, which shielded the surface-attached TATp. At the same time, the administration of pGFP-TATpliposomes with the low pH-detachable PEG resulted in at least three times more efficient transfection since the removal of PEG under the action of the decreased intratumoral pH leads to the exposure of the liposome-attached TATp residues, enhanced penetration of the liposomes inside tumor cells and more effective intracellular delivery of the pGFP. This result can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems.

Cell-penetrating and cell-targeting peptides in drug delivery

“…These chains are attached to the drug-loaded nanoparticle through a pH sensitive linker. Once in the peritumoral environment (see above), the CPP will be exposed upon cleavage of the long PEG chains (from [98]). …”

“…Similarly, Kale et al obtained an enhanced in vivo transfection of DNA using pH-sensitive Tat-modified pegylated (PEG) liposomes ( Figure 1D) [98]. Basically, a number of PEG chains were attached to the liposome surface that contained also some Tat peptides of much smaller size.…”

“…The steric hindrances created by the PEG coat were expected to shield the surface-attached Tat peptides, therefore preventing again the non-specific liposome/cell interactions. Since these long PEG chains were coupled to the liposome surface through a pH-sensitive hydrazone linker, cleavage of the linker could occur only in the acidic environment of the tumor [98]. In experiments performed in tumor-bearing mice, the liposomes were administered directly intra-tumorally, and allowed to obtain at least a three times more efficient transfection than with the corresponding pH-insensitive system.…”

Doxorubicin in TAT peptide-modified multifunctional immunoliposomes demonstrates increased activity against both drug-sensitive and drug-resistant ovarian cancer models

“…Long-chain "shielding" PEG (polyethylene glycol)-PE (phosphatidylethanolamine) conjugate was used in this study with a pH-sensitive bond between PEG and PE, which is stable enough at normal/neutral pH but degrades at the acidic pH characteristic of a tumor extracellular environment. While various pH-sensitive polymers can be used, we have used hydrazone-based polymers successfully in the past [39][40][41] and used them in the present work. In the current study, we used liposomes modified with all three functionalities mentioned above-antibody-targeted, cellpenetrating ability, and shielding/de-shielding capability.…”

Investigation of enzyme-sensitive lipid nanoparticles for delivery of siRNA to blood–brain barrier and glioma cells

“…16,17 To solve this PEGylation dilemma, different strategies have been reported for triggered dePEGylation at the target site. Examples are conjugation of PEG to the nanoparticle through labile linkers, such as disulfide bonds, 18 pH-sensitive groups, 19 or esterasesensitive groups. 20 In addition, the unique pathophysiological conditions of tumors can be exploited to trigger removal of PEG.…”