Triblock Copolymer Nanovesicles for pH-Responsive Targeted Delivery and Controlled Release of siRNA to Cancer Cells

Abstract

New pH-responsive polymersomes for active anticancer oligonucleotide delivery were prepared from triblock copolymers. The delivery systems were formed by two terminal hydrophilic blocks, PEG and polyglycerolmethacrylate (poly-GMA), and a central weakly basic block, polyimidazole-hexyl methacrylate (poly-ImHeMA), which can complex with oligonucleotides and control vesicle formation/disassembly via pH variations. Targeted polymersomes were prepared by mixing folate-derivatized and underivatized copolymers. At pH 5, ds-DNA was found to complex with the pH-responsive copolymers at a N/P molar ratio above ∼2:1, which assisted the encapsulation of ds-DNA in the polymersomes, while low association was observed at pH 7.4. Cytotoxicity studies performed on folate receptor overexpressing KB and B16-F10 cells and low folate receptor expressing MCF-7 cells showed high tolerance of the polymersomes at up to 3 mg/mL concentration. Studies performed with red blood cells showed that at pH 5.0 the polymersomes have endosomolytic properties. Cytofluorimetric studies showed a 5.5-fold higher uptake of ds-DNA loaded folate-functional polymersomes in KB cells compared to nontargeted polymersomes. In addition, ds-DNA was found to be localized both in the nucleus and in the cytosol. The incubation of luciferase transfected B16-F10 cells with targeted polymersomes loaded with luciferase and Hsp90 expression silencing siRNAs yielded 31 and 23% knockdown in target protein expression, respectively.

[Cu(TPMA)(Phen)](ClO4)2: Metallodrug Nanocontainer Delivery and Membrane Lipidomics of a Neuroblastoma Cell Line Coupled with a Liposome Biomimetic Model Focusing on Fatty Acid Reactivity

“… 36 , 37 Indeed, one of the major features of tumor tissues is the acidic extracellular pH that is due to lactate secretion from anaerobic glycolysis. To date, many polymeric pH-responsive delivery systems such as nanoparticles 38 , 39 and micelles 40 , 41 have been developed to take advantage of the pH values related to pathological conditions. These systems present physical properties such as swelling/deswelling, particle disruption and aggregation, and protonation/deprotonation of the main functional groups that change in response to different environmental conditions.…”

Quantification of intracellular payload release from polymersome nanoparticles

“…Modification of the chemical make-up of PMs can lead to alteration of the release kinetics of encapsulated compounds. There are numerous examples of PMs that release their payload in response to stimuli including alterations in pH 5 6 , temperature 7 , oxidation 8 and light 9 10 . This responsiveness can be extended by using variable ratios of blends of different copolymers to tune PM release kinetics 11 .…”

Developing Actively Targeted Nanoparticles to Fight Cancer: Focus on Italian Research

“…FA was linked to the copolymer, via an amide linkage, and a mixture of targeted and untargeted chains was used to prepare polymerosomes that were tested in vitro. The results showed a 5.5-fold higher uptake of double-strand-DNA-loaded folate-polymersomes in KB cells, compared to the untargeted ones [ 53 , 54 ].…”