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

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• 作者：Marian Vila-Caballer^a ; ¹ ; Gaia Codolo^a ; Fabio Munari^b ; Alessio Malfanti^c ; Matteo Fassan^d ; Massimo Rugge^d ; Anna Balasso^c ; Marina de Bernard^a ; ^{marina.debernard@unipd.it" class="auth_mail" title="E-mail the corresponding author} ; Stefano Salmaso^c ; ^{stefano.salmaso@unipd.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：pH-responsive liposomes ; Tumour targeting ; Protein delivery ; Bladder cancer treatment
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 September 2016
• 年：2016
• 卷：238
• 期：Complete
• 页码：31-42
• 全文大小：2114 K

文摘

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 (mPEG_5kDa-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 mPEG_5kDa-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 pH 7.4, 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 pH 6.5, 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 mPEG_5kDa-DSPE/stearoyl-PEG-polySDM/lipid molar ratio liposomes resulted in a time-dependent liposome association with the cells. At pH 7.4, the association of BSA-loaded liposomes with the MB49 cells and macrophages was remarkably lower than at pH 6.5. Confocal images of bladder sections revealed that 2 h after the instillation, liposomes at pH 7.4 and control non-responsive liposomes at pH 7.4 or 6.5 did not associate nor delivered FITC-BSA to the bladder epithelium. On the contrary, the pH-responsive liposome formulation set at pH 6.5 and soon administered to mice by bladder instillation showed that, 2 h after administration, the pH-responsive liposomes efficiently delivered the loaded FITC-BSA to the bladder epithelium.