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

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.

[1]  M. Rouprêt,et al.  Failure of bacille Calmette‐Guérin in patients with high risk non‐muscle‐invasive bladder cancer unsuitable for radical cystectomy: an update of available treatment options , 2010, BJU international.

[2]  S. Cryan,et al.  Targeted Liposomal Drug Delivery to Monocytes and Macrophages , 2010, Journal of drug delivery.

[3]  Z. Gu,et al.  Cholesterol Derivatives Based Charged Liposomes for Doxorubicin Delivery: Preparation, In Vitro and In Vivo Characterization , 2012, Theranostics.

[4]  R. Prassl,et al.  Inhalable liposomal formulation for vasoactive intestinal peptide. , 2008, International journal of pharmaceutics.

[5]  I. Fidler,et al.  Binding of liposomes to human bladder tumor epithelial cell lines: implications for an intravesical drug delivery system for the treatment of bladder cancer. , 1989, Selective cancer therapeutics.

[6]  S. Salmaso,et al.  pH-sensitive stearoyl-PEG-poly(methacryloyl sulfadimethoxine) decorated liposomes for the delivery of gemcitabine to cancer cells. , 2014, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[7]  N. Rioux-Leclercq,et al.  Efficacy of paclitaxel released from bio-adhesive polymer microspheres on model superficial bladder cancer. , 2004, The Journal of urology.

[8]  Photodynamic efficiency of liposome-administered tetramethyl hematoporphyrin in two human bladder cancer cell lines , 2004, Urological Research.

[9]  B. Jefferson,et al.  The Characterization of Feces and Urine: A Review of the Literature to Inform Advanced Treatment Technology , 2015, Critical reviews in environmental science and technology.

[10]  M. Kashyap,et al.  Advances in intravesical therapy for urinary tract disorders , 2016, Expert opinion on drug delivery.

[11]  W. See,et al.  MB49 murine urothelial carcinoma: molecular and phenotypic comparison to human cell lines as a model of the direct tumor response to bacillus Calmette-Guerin. , 2009, The Journal of urology.

[12]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[13]  D. Collins,et al.  Efficient encapsulation of proteins within liposomes for slow release in vivo. , 1994, Biochemical and biophysical research communications.

[14]  Mahavir Singh,et al.  Immunodominant PstS1 antigen of mycobacterium tuberculosis is a potent biological response modifier for the treatment of bladder cancer , 2004, BMC Cancer.

[15]  You Han Bae,et al.  pH-responsive sulfonamide/PEI system for tumor specific gene delivery: an in vitro study. , 2006, Biomacromolecules.

[16]  P. Caliceti,et al.  Star-like oligo-arginyl-maltotriosyl derivatives as novel cell-penetrating enhancers for the intracellular delivery of colloidal therapeutic systems. , 2012, Bioconjugate chemistry.

[17]  V. Bergdall,et al.  Paclitaxel gelatin nanoparticles for intravesical bladder cancer therapy. , 2011, The Journal of urology.

[18]  G. Golomb,et al.  Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[19]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[20]  Lin Mei,et al.  Nanotheranostics ˗ Application and Further Development of Nanomedicine Strategies for Advanced Theranostics , 2014, Theranostics.

[21]  I. Eue,et al.  Growth inhibition of human mammary carcinoma by liposomal hexadecylphosphocholine: Participation of activated macrophages in the antitumor mechanism , 2001, International journal of cancer.

[22]  M. Momin,et al.  INTRAVESICAL DRUG DELIVERY SYSTEM FOR BLADDER: AN OVERVIEW , 2013 .

[23]  D. Lamm,et al.  Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer. , 2014, Urologic oncology.

[24]  Ü. Langel,et al.  Applications of Cell-Penetrating Peptides for Tumor Targeting and Future Cancer Therapies , 2012, Pharmaceuticals.

[25]  M. Yeh,et al.  The treatment of bladder cancer in a mouse model by epigallocatechin-3-gallate-gold nanoparticles. , 2011, Biomaterials.

[26]  M. Knepper,et al.  Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Fan-hua Meng,et al.  Comparison of intravesical bacillus Calmette-Guerin and mitomycin C administration for non-muscle invasive bladder cancer: A meta-analysis and systematic review , 2016, Oncology letters.

[28]  M. Chancellor,et al.  Intravesical liposome drug delivery and IC/BPS , 2015, Translational andrology and urology.

[29]  Todd A. Jackson,et al.  Dietary ammonium chloride for the acidification of mouse urine. , 2009, Journal of the American Association for Laboratory Animal Science.

[30]  Hongwei Jin,et al.  Tumor Imaging and Interferon-γ–Inducible Protein-10 Gene Transfer Using a Highly Efficient Transferrin-Conjugated Liposome System in Mice , 2013, Clinical Cancer Research.

[31]  I. Tannock,et al.  Acid pH in tumors and its potential for therapeutic exploitation. , 1989, Cancer research.

[32]  Gang Zhao,et al.  Molecular targeting of liposomal nanoparticles to tumor microenvironment , 2012, International journal of nanomedicine.

[33]  M. Chancellor,et al.  Liposomal bladder instillations for IC/BPS: an open-label clinical evaluation , 2014, International Urology and Nephrology.

[34]  D. Bostwick,et al.  Treatment of experimental bladder cancer with hyperthermia and phase transition liposomes containing methotrexate. , 1988, The Journal of urology.

[35]  D. Thompson,et al.  Size and structure of spontaneously forming liposomes in lipid/PEG-lipid mixtures. , 2002, Biophysical journal.

[36]  F. Atyabi,et al.  Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice , 2009, Acta pharmaceutica.

[37]  M. D’Elios,et al.  The neutrophil-activating protein of Helicobacter pylori (HP-NAP) as an immune modulating agent. , 2007, FEMS immunology and medical microbiology.

[38]  Zhi-ren Zhang,et al.  Macrophages in Tumor Microenvironments and the Progression of Tumors , 2012, Clinical & developmental immunology.

[39]  David S. Jones,et al.  Mucoadhesive polymeric platforms for controlled drug delivery. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[40]  J. Demengeot,et al.  Regulatory T Cells Accumulate in the Lung Allergic Inflammation and Efficiently Suppress T-Cell Proliferation but Not Th2 Cytokine Production , 2011, Clinical & developmental immunology.

[41]  N. Itano,et al.  Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment , 2014, Cancers.

[42]  S. Lorkowski,et al.  Reduced PMA enhances the responsiveness of transfected THP-1 macrophages to polarizing stimuli. , 2014, Journal of immunological methods.

[43]  Sanyog Jain,et al.  RGD-anchored magnetic liposomes for monocytes/neutrophils-mediated brain targeting. , 2003, International journal of pharmaceutics.

[44]  J. Mes,et al.  Characterization of polarized THP-1 macrophages and polarizing ability of LPS and food compounds. , 2013, Food & function.

[45]  S. Shariat,et al.  Update on intravesical agents for non-muscle-invasive bladder cancer. , 2010, Immunotherapy.

[46]  B. Roy,et al.  Influence of Lipid Composition, pH, and Temperature on Physicochemical Properties of Liposomes with Curcumin as Model Drug. , 2016, Journal of oleo science.

[47]  H. Nishiyama,et al.  The therapeutic effects of R8-liposome-BCG-CWS on BBN-induced rat urinary bladder carcinoma. , 2011, Anticancer research.

[48]  Y. Caplan,et al.  Urine pH: the effects of time and temperature after collection. , 2007, Journal of analytical toxicology.

[49]  Antonio P. Costa,et al.  Protein Encapsulation in Unilamellar Liposomes: High Encapsulation Efficiency and A Novel Technique to Assess Lipid-Protein Interaction , 2012, Pharmaceutical Research.

[50]  G. Gregoriadis.  Liposomes in the therapy of lysosomal storage diseases , 1978, Nature.

[51]  Weijun Su,et al.  CD44 antibody-targeted liposomal nanoparticles for molecular imaging and therapy of hepatocellular carcinoma. , 2012, Biomaterials.

[52]  Wei Tang,et al.  Inhaled corticosteroid influence toll like receptor 2 expression in induced sputum from patients with COPD , 2013, Translational Respiratory Medicine.

[53]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[54]  A. Bangham,et al.  Diffusion of univalent ions across the lamellae of swollen phospholipids. , 1965, Journal of molecular biology.

[55]  V. Torchilin,et al.  Lysosome-targeted octadecyl-rhodamine B-liposomes enhance lysosomal accumulation of glucocerebrosidase in Gaucher's cells in vitro. , 2013, Nanomedicine.

[56]  J. Aguado,et al.  Bacillus Calmette-Guérin (BCG) Infection Following Intravesical BCG Administration as Adjunctive Therapy For Bladder Cancer , 2014, Medicine.

[57]  M. Gleave,et al.  In vivo Evaluation of Mucoadhesive Nanoparticulate Docetaxel for Intravesical Treatment of Non–Muscle-Invasive Bladder Cancer , 2011, Clinical Cancer Research.

[58]  A. Nardin,et al.  Liposomal muramyl tripeptide phosphatidylethanolamine: Targeting and activating macrophages for adjuvant treatment of osteosarcoma. , 2006, Current cancer drug targets.

[59]  J. Lenormand,et al.  Liposomes-mediated delivery of pro-apoptotic therapeutic membrane proteins. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[60]  P. Caliceti,et al.  pH-responsive lipid core micelles for tumour targeting. , 2013, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[61]  P. Sidaway.  Bladder cancer: Atezolizumab effective against advanced-stage disease , 2016, Nature Reviews Urology.

[62]  M. Rugge,et al.  HP-NAP inhibits the growth of bladder cancer in mice by activating a cytotoxic Th1 response , 2011, Cancer Immunology, Immunotherapy.

[63]  C. Sarisozen,et al.  Intravesical cationic nanoparticles of chitosan and polycaprolactone for the delivery of Mitomycin C to bladder tumors. , 2009, International journal of pharmaceutics.

[64]  M. Gleave,et al.  Tissue uptake of docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols and their effects on the morphology of the bladder urothelium. , 2012, Biomaterials.

[65]  J. McKiernan,et al.  A phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. , 2011, The Journal of urology.

[66]  Ze Lu,et al.  Paclitaxel-Loaded Gelatin Nanoparticles for Intravesical Bladder Cancer Therapy , 2004, Clinical Cancer Research.

[67]  P. Caliceti,et al.  Stealth Properties to Improve Therapeutic Efficacy of Drug Nanocarriers , 2013, Journal of drug delivery.

[68]  M. Chancellor,et al.  Development of potential orphan drug therapy of intravesical liposomal tacrolimus for hemorrhagic cystitis due to increased local drug exposure. , 2013, The Journal of urology.

[69]  K. Kurokawa,et al.  The role of phagocytosis in IL-8 production by human monocytes in response to lipoproteins on Staphylococcus aureus. , 2011, Biochemical and biophysical research communications.

[70]  P. Andersen,et al.  Cationic liposomes as vaccine adjuvants , 2007, Expert review of vaccines.

[71]  Shyh-Dar Li,et al.  Thermosensitive liposomes for the delivery of gemcitabine and oxaliplatin to tumors. , 2013, Molecular pharmaceutics.