pH-Triggered Reversible “Stealth” Polycationic Micelles

Abstract

Amphiphilic polycations with a "stealth" cationic nature have been designed and synthesized by the PEGylation of polycationic amphiphile via a novel pH responsible benzoic imine linker. The linkage is stable in aqueous solution at physiological pH but cleaves in slight acidic conditions such as the extracellular environment of solid tumor and endosomes. The polymeric micelle formed from the amphiphilic "stealth" polycation contains a pH-switchable cationic surface driven by the reversible detachment/reattachment of the shielding PEG chains due to the cleavage/formation process of the imine linkage. At physiological pH, the micellar surface was shielded by the PEG corona, leading to lower cytotoxicity and less hemolysis, whereas in a mild acidic condition like in endosomes or solid tumors, the deshielding of the PEG chains exposed the positive charge on the micellar surface and retained the membrane disrupting ability. The amphiphilic "stealth" polycation is potentially useful as a drug targeting system toward tumors via endocytosis and trafficked through the endosomal pathway.

Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-l-lysine nanocarrier to suppress prostate cancer growth in mice

“…These compounds are normally pHtriggered amphiphiles that undergo a surface change in the acidic environment, leading to the release of nanoparticles into the cytoplasm. Previously our group has published the synthesis and characterisation of a new class of 'stealth' amphiphilic PLLs (Gu et al, 2008). These PLLs were chemically modified with cholic acid (CA, a hydrophobic moiety) on one side and subsequently grafted with poly(ethylene glycol) (PEG) on the other side, via a novel acid sensitive linker (benzoic imine) (see Figure 1).…”

pH-sensitive micelles self-assembled from polymer brush (PAE-<em>g</em>-cholesterol)-<em>b</em>-PEG-<em>b</em>-(PAE-<em>g</em>-cholesterol) for anticancer drug delivery and controlled release

“…The pH-sensitivity of the system could be used to realize the drug controlled release. 32,34,36,37 In summary, an ideal pH-sensitive polymeric micelle used as an anticancer drug delivery carrier should possess high drug loading content (LC), long-time circulation, low cytotoxicity, and sharp pH-sensitivity. For example, amphiphilic diblock pH-sensitive polymer poly(β-amino ester)-b-poly(ethylene glycol) (MPEG-b-PAE) was synthesized successfully, and its self-assembled micelle was developed as a carrier for co-delivery of CPT and DOX.…”

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

“…One approach that has been developed to combat this is the addition of a novel pH-sensitive benzoic imine linker between the PEG group and the polymer (e.g. poly-l-lysine) [116] . The linkage is stable in aqueous solution at physiological pH (pH ~7.4) but cleaves in acidic conditions such as the extracellular environment of solid tumour (pH ~6.8) and in endosomes (pH ~5.5).…”

“…When this formulation arrives at the tumour sites via EPR effect, the cationic surface becomes exposed. This is driven by the reversible detachment of the shielding PEG chains due to the processing of the imine linkage, resulting in binding of vectors to the tumour tissues by electrostatic interaction and enhancement of endosomal escape [116,117] .…”