Paclitaxel-loaded cubosome lipid nanocarriers stabilised with pH and hydrogen peroxide-responsive steric stabilisers as drug delivery vehicles.

Responsive nanoparticle delivery systems hold great potential for next-generation chemotherapeutic treatment with reduced off-target side effects. In this work, we formulated responsive lipid-based cubosomes loaded with paclitaxel (PTX) as a model drug and stabilised by novel amphiphilic block copolymers (ABCs) containing the pH-responsive poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) and/or the hydrogen peroxide (H 2 O 2 )-responsive poly(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate) (PTBA) blocks. The results showed that these cubosomes with a particle size of around 250 nm exhibited excellent PTX encapsulation efficiency of up to 60% and had the ability to control the release rate of the drug in response to pH and H 2 O 2 changes. Specifically, compared to the physiological pH of 7.4, PTX was released faster from the cubosome carriers when exposed to pH 5.5 and/or 50 mM H 2 O 2 conditions, which are pathological conditions found in a tumour microenvironment. In vitro cytotoxicity and cell uptake studies further investigated the cellular interactions of these cubosomes. It was found that cubosomes containing PTX had more toxic effects than the control free PTX sample. Compared to cubosomes stabilised by the non-responsive block copolymer Pluronic® F127, the ABC-stabilised cubosomes also had higher cell internalisation efficiency demonstrated by the cytoplasmic fluorescence intensities using confocal microscopy. These results demonstrated that ABCs containing responsive moieties can stabilise lipid cubosomes and enhance controlled release of poorly soluble chemotherapeutics and cellular uptake.