A pH-sensitive stearoyl-PEG-poly(methacryloyl sulfadimethoxine)-decorated liposome system for protein delivery: An application for bladder cancer treatment

Abstract

Stealth pH-responsive liposomes for the delivery of therapeutic proteins to the bladder epithelium were prepared using methoxy-poly(ethylene glycol)5kDa-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (mPEG5kDa-DSPE) and stearoyl-poly(ethylene glycol)-poly(methacryloyl sulfadimethoxine) copolymer (stearoyl-PEG-polySDM), which possesses an apparent pKa of 7.2. Liposomes of 0.2:0.6:100, 0.5:1.5:100 and 1:3:100 mPEG5kDa-DSPE/stearoyl-PEG-polySDM/(soybean phosphatidylcholine+cholesterol) molar ratios were loaded with bovine serum albumin (BSA) as a protein model. The loading capacity was 1.3% w/w BSA/lipid. At pH7.4, all liposome formulations displayed a negative zeta-potential and were stable for several days. By pH decrease or addition to mouse urine, the zeta potential strongly decreased, and the liposomes underwent a rapid size increase and aggregation. Photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM) analyses showed that the extent of the aggregation depended on the stearoyl-PEG-polySDM/lipid molar ratio. Cytofluorimetric analysis and confocal microscopy showed that at pH6.5, the incubation of MB49 mouse bladder cancer cells and macrophages with fluorescein isothiocyanate-labelled-BSA (FITC-BSA) loaded and N-(Lissamine Rhodamine B sulfonyl)-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt (rhodamine-DHPE) labelled 1:3:100 mPEG5kDa-DSPE/stearoyl-PEG-polySDM/lipid molar ratio liposomes resulted in a time-dependent liposome association with the cells. At pH7.4, the association of BSA-loaded liposomes with the MB49 cells and macrophages was remarkably lower than at pH6.5. Confocal images of bladder sections revealed that 2h after the instillation, liposomes at pH7.4 and control non-responsive liposomes at pH7.4 or 6.5 did not associate nor delivered FITC-BSA to the bladder epithelium. On the contrary, the pH-responsive liposome formulation set at pH6.5 and soon administered to mice by bladder instillation showed that, 2h after administration, the pH-responsive liposomes efficiently delivered the loaded FITC-BSA to the bladder epithelium.

Hyaluronic Acid-Based pH-Sensitive Polymer-Modified Liposomes for Cell-Specific Intracellular Drug Delivery Systems

“…[8][9][10][11] To control drug release profiles, external stimuli-sensitive properties such as temperature, pH, magnetic field and light have been applied for nanocarriers. [12][13][14][15][16][17][18][19][20][21] ThermoDox is one example of a temperature-responsive liposome designed to achieve drug release at tumor tissues under local heating of tumor tissues. [22][23][24] Temperature-sensitive polymer-modified liposomes are another platform to develop temperature-responsive liposomes.…”

Rational Design of Nanocarriers for Intracellular Protein Delivery

“…In the meantime, the protein TRAIL was encapsulated in the outer shell. [97] Results revealed that the BSA-loaded liposomes were colloidally stable at neural pH but showed remarkably high adhesion with MB49 cells and more effective administration to mice via bladder instillation under acidic environment. In vitro and in vivo experiment demonstrated that this multifunctional codelivery gel-liposome system showed significant inhibition of the tumor growth in the MDA-MB-231 xenograft tumor animal model.…”

“…[94] Herein, the Dox was first encapsulated into CPP (R8H3) modified liposome. [91,97,98] For instance, Opanasopit and co-workers synthesized methylated N-(4-N,N-dimethylaminobenzyl) CS, which is water soluble at physiological pH. In the meantime, the protein TRAIL was encapsulated in the outer shell.…”

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

“…They demonstrated that the liposomes which carried negative charges at physiological condition underwent a rapid size increase and aggregation at pH 6.5 due to the decreased zeta potential. Cytofluorimetric analysis and confocal microscopy results showed that at pH 6.5, fluorescein isothiocyanate‐labelled‐BSA (FITC‐BSA) loaded and N‐(Lissamine Rhodamine B sulfonyl)‐1, 2‐dihexadecanoyl‐sn‐glycero‐3‐phosphoethanolamine triethylammonium salt (rhodamine‐DHPE) labeled liposomes more efficiently associated with MB49 mouse bladder cancer cells and macrophages cells than at pH 7.4 . Yung et al.…”