Gemcitabine-loaded innovative nanocarriers vs GEMZAR: Biodistribution, pharmacokinetic features and in vivo antitumor activity

Expert Opinion on Drug Delivery

Volumn 8, Issue 12, 2011, Pages 1609-1629

  Celia, Christian ^a   Cosco, Donato ^b   Paolino, Donatella ^b,c   Fresta, Massimo ^b,c  

^a HOUSTON METHODIST RESEARCH INSTITUTE   (United States)

^b UNIVERSITY MAGNA GRAECIA OF CATANZARO   (Italy)

^c UOC Farmacia Ospedaliera   (Italy)

Author keywords

Gemcitabine; Liposomes; Polymeric nanoparticles; Squalenoylation

Indexed keywords

ACRYLIC ACID DERIVATIVE; ALPHA,BETA POLYASPARTYL[(HYDRAZIDE) CO(BUTYRYLHYDRAZIDE)]COPOLYMER; AMMONIUM SULFATE; APOLIPOPROTEIN; CATHEPSIN B; CATHEPSIN D; CHITOSAN; CISPLATIN; COPOLYMER; CYTARABINE; CYTIDINE DEAMINASE; DOCETAXEL; DOXORUBICIN; FLOXURIDINE; GEMCITABINE; IRINOTECAN; LIPOSOME; LOW DENSITY LIPOPROTEIN RECEPTOR; MACROGOL; MATRIGEL; NANOCARRIER; NANOPARTICLE; OPSONIN; PACLITAXEL; POLY(BUTYL 2 CYANOACRYLATE); POLY(ETHYLENE GLYCOL)BLOCK POLY(DEXTRO LEVO LACTIDE); POLYMER; SQUALENE; TRASTUZUMAB; UNCLASSIFIED DRUG; VINDESINE;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; AQUEOUS SOLUTION; BIOAVAILABILITY; BIOCOMPATIBILITY; BLADDER CANCER; BLOOD BRAIN BARRIER; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER SURVIVAL; CELL CYCLE ARREST; CELL VIABILITY; COLLOID; CYTOTOXICITY; DILUTION; DRUG ABSORPTION; DRUG ACCUMULATION; DRUG BLOOD LEVEL; DRUG DELIVERY SYSTEM; DRUG DISTRIBUTION; DRUG DNA INTERACTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG EXTRAVASATION; DRUG FORMULATION; DRUG HALF LIFE; DRUG PENETRATION; DRUG POTENTIATION; DRUG RELEASE; DRUG SENSITIVITY; DRUG STABILITY; DRUG TRANSPORT; DRUG UPTAKE; ENCAPSULATION; ENDOCYTOSIS; ENZYMATIC DEGRADATION; ENZYME METABOLISM; GENOTYPE; GLIOMA; GLOMERULUS FILTRATION; HEALTH CARE COST; HISTOLOGY; HUMAN; HYDROPHILIC CONTACT LENS; HYDROPHILICITY; HYDROPHOBICITY; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; IN VIVO STUDY; ISOTOPE LABELING; LEUKEMIA; LIPOPHILICITY; LIPOSOMAL DELIVERY; METASTASIS; MOLECULAR WEIGHT; NONHUMAN; OPSONIZATION; PANCREAS CARCINOMA; PARTICLE SIZE; PATIENT COMPLIANCE; PH; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHYSICAL CHEMISTRY; POLYMERIZATION; PROTON TRANSPORT; QUALITY OF LIFE; RETICULOENDOTHELIAL SYSTEM; REVIEW; SHELF LIFE; SUPRAMOLECULAR VESICULAR DEVICE; THROMBOSIS; TUMOR GROWTH; TUMOR VOLUME; VASCULAR DISEASE; XENOGRAFT;

ANIMALS; ANTIMETABOLITES, ANTINEOPLASTIC; DEOXYCYTIDINE; DRUG CARRIERS; HUMANS; LIPOSOMES; NANOPARTICLES; NEOPLASMS; POLYMERS; SQUALENE; TISSUE DISTRIBUTION;

EID: 81855228063     PISSN: 17425247     EISSN: 17447593     Source Type: Journal    
DOI: 10.1517/17425247.2011.632630     Document Type: Review

References (112)

1. Petzinger E, Ziegler K. Ochratoxin A from a toxicological perspective. J Vet Pharmacol Ther 2000;23:91-8 (Pubitemid 30348766)
2. Wogan GN, Hecht SS, Felton JS, et al. Environmental and chemical carcinogenesis. Semin Cancer Biol 2004;14:473-86 (Pubitemid 39360995)
3. Qazi A, Pal J, Maitah M, et al. Anticancer activity of a broccoli derivative, sulforaphane, in barrett adenocarcinoma: potential use in chemoprevention and as adjuvant in chemotherapy. Transl Oncol 2010;3:389-99
4. Shukla Y, Singh R. Resveratrol and cellular mechanisms of cancer prevention. Ann N Y Acad Sci 2011;1215:1-8
5. Sadiq AA, Patel MR, Jacobson BA, et al. Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II. Invest New Drugs 2010;28:20-5
6. van de Steeg E, van Esch A, Wagenaar E, et al. High impact of oatp1a/1b transporters on in vivo disposition of the hydrophobic anticancer drug Paclitaxel. Clin Cancer Res 2011;17: 294-301
7. Hu CB, Chen CP, Yeh TK, et al. BPR0C261 is a novel orally active antitumor agent with antimitotic and anti-angiogenic activities. Cancer Sci 2011;102:182-91
8. Khadka DB, Cho WJ. 3-Arylisoquinolines as novel topoisomerase I inhibitors. Bioorg Med Chem 2011;19: 724-34
9. Heinemann V. Gemcitabine: progress in the treatment of pancreatic cancer. Oncology 2001; 60: 8-18 (Pubitemid 32041425)
10. Hui YF, Reitz J. Gemcitabine: a cytidine analogue active against solid tumors. Am J Health Syst Pharm 1997;54:162-70 (Pubitemid 27058210)
11. Bouffard DY, Laliberte J, Momparler RL. Kinetic studies on 2',2'-difluorodeoxycytidine (gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochem Pharmacol 1993;45:1857-61 (Pubitemid 23150977)
12. Reid JM, Qu W, Sa$L, et al. Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid tumors. J Clin Oncol 2004;22:2445-51 (Pubitemid 41115403)
13. Moog R, Burger AM, Brandl M, et al. Change in pharmacokinetic and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels. Cancer Chemother Pharmacol 2002;49:356-66 (Pubitemid 34439336)
14. Boven E, Schipper H, Erkelens CA, et al. The influence of the schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer. Br J Cancer 1993;68:52-6 (Pubitemid 23178550)
15. Braakhuis BJ, Ruiz van Haperen VW, Welters MJ, Peters GJ. Schedule-dependent therapeutic efficacy of the combination of gemcitabine and cisplatin in head and neck cancer xenografts. Eur J Cancer 1995;31A:2335-40 (Pubitemid 26050580)
16. Dasanu CA. Gemcitabine: vascular toxicity and prothrombotic potential. Expert Opin Drug Saf 2008;7:703-6
17. Mini E, Nobili S, Caciagli B, et al. Cellular pharmacology of gemcitabine. Ann Oncol 2006;17(Suppl 5):v7-v12 (Pubitemid 43994854)
18. Ueno H, Kiyosawa K, Kaniwa N. Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy? Br J Cancer 2007;97:145-51 (Pubitemid 47057479)
19. Gati WP, Paterson ARP, Laratt LM, et al. Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular es nucleoside transporter site content by flow cytometry with SAENTA-fluorescein. Blood 1997;90:346-53 (Pubitemid 27276580)
20. Hammond JR, Lee S, Ferguson J. [3H] Gemcitabine uptake by nucleoside transporters in a human head and neck squamous carcinoma cell line. Pharmacol Exp Ther 1999;288:1185-91 (Pubitemid 29254157)
21. Rauchwerger DR, Firby PS, Hedley DW, Moore MJ. Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity. Cancer Res 2000;60:6075-9
22. Bhutia YD, Hung SW, Patel B, et al. CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells. Cancer Res 2011;71:1825-35
23. Bergman AM, Munch-Petersen B, Jensen PB, et al. Collateral sensitivity to gemcitabine (2',2'-difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines. Biochem Pharmacol 2001;61:1401-8 (Pubitemid 32452356)
24. Zhang X, Yashiro M, Qiu H, et al. Establishment and characterization of multidrug-resistant gastric cancer cell lines. Anticancer Res 2010;30:915-21
25. Bergman AM, Pinedo HM, Peters GJ. Determinants of resistance to 2',2'-difluorodeoxycytidine (gemcitabine). Drug Resist Updat 2002;5:19-33
26. Ohhashi S, Ohuchida K, Mizumoto K, et al. Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer. Anticancer Res 2008;28:2205-12
27. Celia C, Calvagno MG, Paolino D, et al. Improved in vitro anti-tumoral activity, intracellular uptake and apoptotic induction of gemcitabine-loaded pegylated unilamellar liposomes. J Nanosci Nanotechnol 2008;8:2102-13
28. Celia C, Malara N, Terracciano R, et al. Liposomal delivery improves the growth-inhibitory and apoptotic activity of low doses of gemcitabine in multiple myeloma cancer cells. Nanomedicine 2008;4:155-66
29. Celano M, Calvagno MG, Bulotta S, et al. Cytotoxic effects of gemcitabine-loaded liposomes in human anaplastic thyroid carcinoma cells. BMC Cancer 2004;4:63
30. Cosco D, Bulotta A, Ventura M, et al. In vivo activity of gemcitabine-loaded PEGylated small unilamellar liposomes against pancreatic cancer. Cancer Chemother Pharmacol 2009;64:1009-20
31. Paolino D, Cosco D, Racanicchi L, et al. Gemcitabine-loaded PEGylated unilamellar liposomes vs GEMZAR: biodistribution, pharmacokinetic features and in vivo antitumor activity. J Control Release 2010;144:144-50
32. GEMZAR and GEM-loaded PEGylated unilamellar liposomes. Uramoto H, Nakanishi R, Nagashima A, et al. A randomized phase II trial of adjuvant chemotherapy with bi-weekly carboplatin plus paclitaxel versus carboplatin plus gemcitabine in patients with completely resected non-small cell lung cancer. Anticancer Res 2010;30:4695-9
33. Gruenberger B, Schueller J, Heubrandtner U, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 2010;11:1142-8
34. Kato K, Nakanishi M, Kaneda Y, et al. Expression of hepatitis B virus surface antigen in adult rat liver. Co-introduction of DNA and nuclear protein by a simplified liposome method. J Biol Chem 1991;266:3361-4 (Pubitemid 21909217)
35. Schiffelers RM, Storm G, ten Kate MT, et al. Liposome-enabled synergistic interaction of antimicrobial agents. J Liposome Res 2002;12:121-7 (Pubitemid 34846963)
36. Pakunlu RI, Cook TJ, Minko T. Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin. Pharm Res 2003;20:351-9 (Pubitemid 36288363)
37. Abraham SA, Mc Kenzie C, Masin D, et al. In vitro and in vivo characterization of doxorubicin and vincristine coencapsulated within liposomes through use of transition metal ion complexation and p H gradient loading. Clin Cancer Res 2004;10:728-38 (Pubitemid 38174011)
38. Tardi PG, Gallagher RC, Johnstone S, et al. Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo. Biochim Biophys Acta 2007;1768:678-87 (Pubitemid 46275599)
39. Tardi PG, Dos Santos N, Harasym TO, et al. Drug ratio-dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo. Mol Cancer Ther 2009;8:2266-75
40. Harasym TO, Tardi PG, Harasym NL, et al. Increased preclinical efficacy of irinotecan and floxuridine coencapsulated inside liposomes is associated with tumor delivery of synergistic drug ratios. Oncol Res 2007;16:361-74 (Pubitemid 47413252)
41. Batist G, Gelmon KA, Chi KN, et al. Safety, pharmacokinetics, and efficacy of CPX-1 liposome injection in patients with advanced solid tumors. Clin Cancer Res 2009;15:692-700
42. Zhang H, Wang G, Yang H. Drug delivery systems for differential release in combination therapy. Expert Opin Drug Deliv 2011;8:171-90
43. Calvagno MG, Cosco D, Celia C, et al. Liposomal multidrug carriers encapsulating gemcitabine and paclitaxel for the treatment of multi-drug resistent tumors. 33rd Annual Meeting & Exposition of the Controlled Realease Society; 2006.
44. Vienna Cosco D, Paolino D, Maiuolo J, et al. Liposomes as multicompartmental carriers for multidrug delivery in anticancer chemotherapy. Drug Deliv Transl Res 2011;1:66-75
45. Drummond DC, Meyer O, Hong K, et al. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 1999;51: 691-743
46. Knop K, Hoogenboom R, Fischer D, Schubert US. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed Engl 2010;49:6288-308
47. Hamidi M, Azadi A, Rafiei P. Pharmacokinetic consequences of pegylation. Drug Deliv 2006;13:399-409 (Pubitemid 44470219)
48. Gregoriadis G. The carrier potential of liposomes in biology and medicine (second of two parts). N Engl J Med 1976;295:765-70
49. Pasut G, Veronese FM. PEGylation for improving the effectiveness of therapeutic biomolecules. Drugs Today (Barc) 2009;45:687-95
50. Klibanov AL, Maruyama K, Torchilin VP, Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 1990;268:235-7 (Pubitemid 20233874)
51. Pasut G, Veronese FM. Polymer drug conjugation, recent achievements and general strategies. Prog Polym Sci 2007;32:933-61 (Pubitemid 47198290)
52. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005;4:145-60 (Pubitemid 40282557)
53. Calvagno MG, Celia C, Paolino D, et al. Effects of lipid composition and preparation conditions on physical-chemical properties, technological parameters and in vitro biological activity of gemcitabine-loaded liposomes. Curr Drug Deliv 2007;4:89-101 (Pubitemid 46066418)
54. Nagayasu A, Uchiyama K, Kiwada H. The size of liposomes: a factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs. Adv Drug Deliv Rev 1999;40:75-87 (Pubitemid 29486605)
55. Kono K, Nakashima S, Kokuryo D, et al. Multi-functional liposomes having temperature-triggered release and magnetic resonance imaging for tumor-specific chemotherapy. Biomaterials 2011;32:1387-95
56. Gabizon A, Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA 1988;85:6949-53
57. Heurtault B, Frisch B, Pons F. Liposomes as delivery systems for nasal vaccination: strategies and outcomes. Expert Opin Drug Deliv 2010;7:829-44
58. Brusa P, Immordino ML, Rocco F, Cattel L. Antitumor activity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. Anticancer Res 2007;27:195-9
59. Falchi L, Gunnellini M, Franco L, et al. Rapid and sustained response of an intra-and extracranial large cell lymphoma mass to liposomal intrathecal Ara-C and R-Mega CEOP systemic chemotherapy. J Neurooncol 2010;97:53-7
60. Reddy LH, Couvreur P. Novel approaches to deliver gemcitabine to cancers. Curr Pharm Des 2008;14:1124-37 (Pubitemid 351982559)
61. Moog R, Burger AM, Brandl M, et al. Change in pharmacokinetic and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels. Cancer Chemother Pharmacol 2002;49:356-66 (Pubitemid 34439336)
62. Immordino ML, Brusa P, Rocco F, et al. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. J Control Release 2004;100:331-46 (Pubitemid 39572916)
63. Fritze A, Hens F, Kimpfler A, et al. Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient. Biochim Biophys Acta 2006;175 8: 1 633-40 (Pubitemid 44466698)
64. Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomed 2006;1(3):297-315
65. Pasut G, Canal F, Dalla Via L, et al. Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid. J Control Release 2008;127:239-48
66. Paolino D, Cosco D, Licciardi M, et al. Polyaspartylhydrazide copolymer-based supramolecular vesicular aggregates as delivery devices for anticancer drugs. Biomacromolecules 2008;9:1117-30 (Pubitemid 351639563)
67. Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991; 9:491-8
68. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986;46:6387-92 (Pubitemid 17221789)
69. Kim IY, Kang YS, Lee DS, et al. Antitumor activity of EGFR targeted p H-sensitive immunoliposomes encapsulating gemcitabine in A549 xenograft nude mice. J Control Release 2009;140:55-60
70. Discher D, Ahmed F. Polymersomes. Annu Rev Biomed Eng 2006;8:323-41 (Pubitemid 44314820)
71. Ahmed F, Pakunlu RI, Brannan A, et al. Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, i nducing apoptosis in proportion to accumulated drug. J Control Release 2006;116:150-8 (Pubitemid 44868999)
72. Licciardi M, Paolino D, Celia C, et al. Folate-targeted supramolecular vesicular aggregates based on polyaspartyl- hydrazide copolymers for the selective delivery of antitumoral drugs. Biomaterials 2010;31:7340-54
73. Storm G, ten Kate MT, Working PK, Bakker-Woudenberg IA Doxorubicin entrapped in sterically stabilized liposomes: effects on bacterial blood clearance capacity of the mononuclear phagocyte system. Clin Cancer Res 1998;4:111-15 (Pubitemid 28062884)
74. Bornmann C, Graeser R, Esser N, et al. A new liposomal formulation of gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging. Cancer Chemother Pharmacol 2008;61:395-405 (Pubitemid 350275974)
75. Bougard F, Giacomelli C, Mespouille L, et al. Influence of the macromolecular architecture on the self-assembly of amphiphilic copolymers based on poly (N, N-dimethylamino-2-ethyl methacrylate) and poly(epsilon- caprolactone). Langmuir 2008;24:8272-9
76. Reddy LH, Couvreur P. Squalene: a natural triterpene for use in disease management and therapy. Adv Drug Deliv Rev 2009;61:1412-26
77. Castelli F, Sarpietro MG, Ceruti M, et al. Characterization of lipophilic gemcitabine prodrug-liposomal membrane interaction by differential scanning calorimetry. Mol Pharm 2006;3:737-44 (Pubitemid 46087489)
78. Couvreur P, Stella B, Reddy LH, et al. Squalenoyl nanomedicines as potential therapeutics. Nano Lett 2006;6:2544-8 (Pubitemid 46076946)
79. Couvreur P, Reddy LH, Mangenot S, et al. Discovery of new hexagonal supramolecular nanostructures formed by Squalenoylation of an anticancer nucleoside analogue. Small 2008;4:247-53 (Pubitemid 351271158)
80. Reddy LH, Dubernet C, Mouelhi SL, et al. A new nanomedicine of gemcitabine displays enhanced anticancer activity in sensitive and resistant leukemia types. J Control Release 2007;124:20-7 (Pubitemid 350103730)
81. Huber-Ruano I, Pastor-Anglada M. Transport of nucleoside analogs across the plasma membrane: a clue to understanding drug-induced cytotoxicity. Curr Drug Metab 2009;10:347-58
82. Ferrandina G, Mey V, Nannizzi S, et al. Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother Pharmacol 2010;65:679-86
83. Perez-Torras S, Garcia-Manteiga J, Mercade E, et al. Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1 (h ENT1) enhances gemcitabine response in human pancreatic cancer. Biochem Pharmacol 2008;76:322-9
84. Mackey JR, Mani RS, Selner M, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 1998;58:4349-57 (Pubitemid 28450036)
85. Gusella M, Pasini F, Bolzonella C, et al. Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours. Br J Clin Pharmacol 2011;71:437-44
86. Spratlin J, Sangha R, Glubrecht D, et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res 2004;10:6956-61 (Pubitemid 39383046)
87. Bildstein L, Dubernet C, Marsaud V, et al. Transmembrane diffusion of gemcitabine by a nanoparticulate squalenoyl prodrug: an original drug delivery pathway. J Control Release 2010;147:163-70
88. Kos J, Sekirnik A, Premzl A, et al. Carboxypeptidases cathepsins X and B display distinct protein profile in human cells and tissues. Exp Cell Res 2005;306:103-13 (Pubitemid 40692776)
89. Reddy LH, Khoury H, Paci A, et al. Squalenoylation favorably modifies the in vivo pharmacokinetics and biodistribution of gemcitabine in mice. Drug Metab Dispos 2008;36:1570-7
90. Reddy LH, Marque PE, Dubernet C, et al. Preclinical toxicology (subacute and acute) and efficacy of a new squalenoyl gemcitabine anticancer nanomedicine. J Pharmacol Exp Ther 2008;325: 484-90 (Pubitemid 351574820)
91. Bildstein L, Hillaireau H, Desmaele D, et al. Freeze-drying of squalenoylated nucleoside analogue nanoparticles. Int J Pharm 2009;381:140-5
92. Reddy LH, Renoir JM, Marsaud V, et al. Anticancer efficacy of squalenoyl gemcitabine nanomedicine on 60 human tumor cell panel and on experimental tumor. Mol Pharm 2009;6:1526-35
93. Paolino D., Cosco D., Cilurzo F., Fresta M. Innovative drug delivery systems for the administration of natural compounds. Curr Bioact Compds 2007;3:262-77
94. Cosco D, Celia C, Cilurzo F, et al. Colloidal Carriers for the enhanced delivery through the skin. Expert Opin Drug Deliv 2008;5:737-55
95. Stella B, Arpicco S, Rocco F, et al. Encapsulation of gemcitabine lipophilic derivatives into polycyanoacrylate nanospheres and nanocapsules. Int J Pharm 2007;344:71-7 (Pubitemid 47464827)
96. Li JM, Chen W, Wang H, et al. Preparation of albumin nanospheres loaded with gemcitabine and their cytotoxicity against BXPC-3 cells in vitro. Acta Pharmacol Sin 2009;30:1337-43
97. Jia L, Zheng JJ, Jiang SM, Huang KH. Preparation, physicochemical characterization and cytotoxicity in vitro of gemcitabine-loaded PEG- PDLLA nanovesicles. World J Gastroenterol 2010;16:1008-13
98. Iannone M, Cosco D, Cilurzo F, et al. A novel animal model to evaluate the ability of a drug delivery system to promote the passage through the BBB. Neurosci Lett 2010;469:93-6
99. Celia C, Cosco D, Paolino D, Fresta M. Nanoparticulate devices for brain drug delivery. Med Res Rev 2011;31:716-56
100. Wang CX, Huang LS, Hou LB, et al. Antitumor effects of polysorbate-80 coated gemcitabine polybutylcyanoacrylate nanoparticles in vitro and its pharmacodynamics in vivo on C6 glioma cells of a brain tumor model. Brain Res 2009;1261:91-9
101. Kim HR, Andrieux K, Gil S, et al. Translocation of poly(ethylene glycol-co- hexadecyl)cyanoacrylate nanoparticles into rat brain endothelial cells: role of apolipoproteins in receptor-mediated endocytosis. Biomacromolecules 2007;8:793-9 (Pubitemid 46488459)
102. Arias JL, Reddy LH, Couvreur P. Superior preclinical efficacy of gemcitabine developed as chitosan nanoparticulate system. Biomacromolecules 2011;12:97-104
103. Arya G, Vandana M, Acharya S, Sahoo SK. Enhanced antiproliferative activity of Herceptin (HER2)-conjugated gemcitabine-loaded chitosan nanoparticle in pancreatic cancer therapy. Nanomedicine 2011; In press
104. Nakai Y, Isayama H, Sasaki T, et al. Impact of S-1 on the survival of patients with advanced pancreatic cancer. Pancreas 2010;39:989-93
105. Ricciardi S, Mey V, Nannizzi S, et al. Synergistic cytotoxicity and molecular interaction on drug targets of sorafenib and gemcitabine in human pancreas cancer cells. Chemotherapy 2010;56:303-12
106. Trodella L, D'Angelillo RM, Ramella S, et al. Chemo-radiotherapy in non-small cell lung cancer: the role of gemcitabine. Ann Oncol 2006;17(Suppl 5):v52-4 (Pubitemid 43985205)
107. Nuijten M, Heigener DF, Bischoff HG, et al. Effectiveness of bevacizumab- and pemetrexed-cisplatin treatment for patients with advanced non-squamous non-small cell lung cancer. Lung Cancer 2010;69(Suppl1):S4-10
108. Jones J, Takeda A, Tan SC, et al. Gemcitabine for the treatment of metastatic breast cancer. Health Technol Assess 2009;13(Suppl 2):1-7
109. Koshy N, Quispe D, Shi R, et al. Cisplatin-gemcitabine therapy in metastatic breast cancer: improved outcome in triple negative breast cancer patients compared to non-triple negative patients. Breast 2010;19:246-8
110. Albain KS, Nag SM, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel versus paclitaxelmonotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2008;26:3950-7
111. Gontero P, Cattel L, Paone TC, et al. Pharmacokinetic study to optimize the intravesical administration of gemcitabine. BJU Int 2010;106:1652-6
112. Pouessel D, Huguet H, Iborra F, et al. A pilot study of gemcitabine in combination with oxaliplatin and vinorelbine in patients with metastatic bladder cancer. Anticancer Res 2010;30:4711-15