Gemcitabine (Gem) is a standard first-line treatment for pancreatic cancer (PC). However, its chemotherapeutic efficacy is hampered by various limitations such as short half-life, metabolic inactivation, and lack of tumor localizing. We previously synthesized a lipophilic Gem derivative (Gem formyl hexadecyl ester, GemC16) that exhibited improved antitumor activity in vitro. In this study, a target ligand N,N-dimethyl-1,3-propanediamine was conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[hydroxyl succinimidyl (polyethylene glycol-2000)] (DSPE-PEG-NHS) to form DSPE-PEG-2N. Then, pancreas-targeting liposomes (2N-LPs) were prepared using the film dispersion-ultrasonic method. GemC16-loaded 2N-LPs displayed near-spherical shapes with an average size distribution of 157.2 nm (polydispersity index (PDI) = 0.201). The encapsulation efficiency of GemC16 was up to 97.3% with a loading capacity of 8.9%. In human PC cell line (BxPC-3) and rat pancreatic acinar cell line (AR42J), cellular uptake of 2N-LPs was significantly enhanced compared with that of unmodified PEG-LPs. 2N-LPs exhibited more potent in vitro cytotoxicity against BxPC-3 and AR42J cell lines than PEG-LPs. After systemic administration in mice, 2N-LPs remarkably increased drug distribution in the pancreas. In an orthotopic tumor mouse model of PC, GemC16-bearing liposomes were more effective in preventing tumor growth than free GemC16. Among these treatments, 2N-LPs showed the best curative effect. Together, 2N-LPs represent a promising nanocarrier to achieve pancreas-targeting drug delivery, and this work would provide new ideas for the chemotherapy of PC.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $57.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: Cancer J Clin. 2010;60:277–300.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.
Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther. 2015;9:3529–45.
Tran B, Whiteman DC, Webb PM, Fritschi L, Fawcett J, Risch HA, et al. Association between ultraviolet radiation, skin sun sensitivity and risk of pancreatic cancer. Cancer Epidemiol. 2013;37:886–92.
Bockhorn M, Uzunoglu FG, Adham M, Imrie C, Milicevic M, Sandberg AA, et al. Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2014;155:977–88.
Ahlgren JD. Chemotherapy for pancreatic carcinoma. Cancer. 1996;78:654–63.
Bria E, Carlini P, Gelibter A, Ruggeri E, Ceribelli A, Pino M, et al. Current status of targeted agents in advanced pancreatic cancer (APC): a pooled analysis of 2,361 patients (pts) enrolled in six phase III trials. J Clin Oncol. 2006;24:4126.
Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 2010;7:163–72.
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–20.
Corsini MM, Miller RC, Haddock MG, Donohue JH, Farnell MB, Nagorney DM, et al. Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975-2005). J Clin Oncol. 2008;26:3511–6.
Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200–10.
Amedei A, Niccolai E, Prisco D. Pancreatic cancer: role of the immune system in cancer progression and vaccine-based immunotherapy. Hum Vaccin Immunother. 2014;10:3354–68.
Brown K, Dixey M, Weymouth-Wilson A, Linclau B. The synthesis of gemcitabine. Carbohydr Res. 2014;387:59–73.
Baraniak J, Pietkiewicz A, Kaczmarek R, Radzikowska E, Kulik K, Krolewska K, et al. N-Acyl-phosphoramidates as potential novel form of gemcitabine prodrugs. Bioorg Med Chem. 2014;22:2133–40.
Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol. 1995;22:3–10.
Cattel L, Airoldi M, Delprino L, Passera R, Milla P, Pedani F. Pharmacokinetic evaluation of gemcitabine and 2’,2’-difluorodeoxycytidine-5’-triphosphate after prolonged infusion in patients affected by different solid tumors. Ann Oncol. 2006;17(Suppl 5):142–7.
Song W, Tang Z, Li M, Lv S, Sun H, Deng M, et al. Polypeptide-based combination of paclitaxel and cisplatin for enhanced chemotherapy efficacy and reduced side-effects. Acta Biomater. 2014;10:1392–402.
Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 1998;58:4349–57.
Oluwasanmi A, Al-Shakarchi W, Manzur A, Aldebasi MH, Elsini RS, Albusair MK, et al. Diels Alder-mediated release of gemcitabine from hybrid nanoparticles for enhanced pancreatic cancer therapy. J Control Release. 2017;266:355–64.
Pratt SE, Durland-Busbice S, Shepard RL, Donoho GP, Starling JJ, Wickremsinhe ER, et al. Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts. Mol Cancer Ther. 2013;12:481–90.
Han H, Jin Q, Wang Y, Chen Y, Ji J. The rational design of a gemcitabine prodrug with AIE-based intracellular light-up characteristics for selective suppression of pancreatic cancer cells. Chem Commun. 2015;51:17435–8.
Abu-Fayyad A, Nazzal S. Gemcitabine-vitamin E conjugates: synthesis, characterization, entrapment into nanoemulsions, and in-vitro deamination and antitumor activity. Int J Pharm. 2017;528:463–70.
Mura S, Bui DT, Couvreur P, Nicolas J. Lipid prodrug nanocarriers in cancer therapy. J Control Release. 2015;208:25–41.
May JP, Undzys E, Roy A, Li SD. Synthesis of a gemcitabine prodrug for remote loading into liposomes and improved therapeutic effect. Bioconjug Chem. 2016;27:226–37.
Nesbitt H, Sheng Y, Kamila S, Logan K, Thomas K, Callan B, et al. Gemcitabine loaded microbubbles for targeted chemo-sonodynamic therapy of pancreatic cancer. J Control Release. 2018;279:8–16.
Cattel L, Ceruti M, Dosio F. From conventional to stealth liposomes: a new frontier in cancer chemotherapy. Tumori. 2003;89:237–49.
Mu LM, Ju RJ, Liu R, Bu YZ, Zhang JY, Li XQ, et al. Dual-functional drug liposomes in treatment of resistant cancers. Adv Drug Deliv Rev. 2017;115:46–56.
Patel KR, Baldeschwieler JD. Treatment of intravenously implanted Lewis lung carcinoma with liposome-encapsulated cytosine arabinoside and non-specific immunotherapy. Int J Cancer. 1984;34:415–20.
Immordino ML, Brusa P, Rocco F, Arpicco S, Ceruti M, Cattel L. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. J Control Release. 2004;100:331–46.
Crosasso P, Brusa P, Dosio F, Arpicco S, Pacchioni D, Schuber F, et al. Antitumoral activity of liposomes and immunoliposomes containing 5-fluorouridine prodrugs. J Pharm Sci. 1997;86:832–9.
Li PW, Guo L, Deng L, Wang L, Luo S, Du ZW, et al. Study on the synthesis and in vitro anti-tumor activity of gemcitabine derivative. West China J Pharm Sci. 2018;3:122–5.
Sloat BR, Sandoval MA, Li D, Chung WG, Lansakara PD, Proteau PJ, et al. In vitro and in vivo anti-tumor activities of a gemcitabine derivative carried by nanoparticles. Int J Pharm. 2011;409:278–88.
Ngoune R, Peters A, von Elverfeldt D, Winkler K, Putz G. Accumulating nanoparticles by EPR: a route of no return. J Control Release. 2016;238:58–70.
Hosoki T. Dynamic CT of pancreatic tumors. AJR Am J Roentgenol. 1983;140:959–65.
Sofuni A, Iijima H, Moriyasu F, Nakayama D, Shimizu M, Nakamura K, et al. Differential diagnosis of pancreatic tumors using ultrasound contrast imaging. J Gastroenterol. 2005;40:518–25.
Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM, et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell. 2009;16:510–20.
Yamamoto K, Som P, Srivastava SC, Meinken GE, Brill AB. Pancreas accumulation of radioiodinated HIPDM in mice and rats. J Nucl Med. 1985;26:765–9.
Yamamoto K, Shibata T, Saji H, Kubo S, Aoki E, Fujita T, et al. Human pancreas scintigraphy using iodine-123-labeled HIPDM and SPECT. J Nucl Med. 1990;31:1015–9.
Li J, Zhang J, Fu Y, Sun X, Gong T, Jiang J, et al. Dual pancreas- and lung-targeting therapy for local and systemic complications of acute pancreatitis mediated by a phenolic propanediamine moiety. J Control Release. 2015;212:19–29.
Luo S, Li P, Li S, Du Z, Hu X, Fu Y, et al. N,N-dimethyl tertiary amino group mediated dual pancreas- and lung-targeting therapy against acute pancreatitis. Mol Pharm. 2017;14:1771–81.
Li M, Tang Z, Lv S, Song W, Hong H, Jing X, et al. Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin. Biomaterials. 2014;35:3851–64.
Moreno JA, Sanchez A, Hoffman RM, Nur S, Lambros MP. Fluorescent orthotopic mouse model of pancreatic cancer. J Vis Exp. 2016;115:1–5.
Aoki H, Aoki M, Katsuta E, Ramanathan R, Idowu MO, Spiegel S, et al. Host sphingosine kinase 1 worsens pancreatic cancer peritoneal carcinomatosis. J Surg Res. 2016;205:510–7.
Zhou M, Li J, Li C, Guo L, Wang X, He Q, et al. Tertiary amine mediated targeted therapy against metastatic lung cancer. J Control Release. 2016;241:81–93.
Wang Y, Fan W, Dai X, Katragadda U, McKinley D, Teng Q, et al. Enhanced tumor delivery of gemcitabine via PEG-DSPE/TPGS mixed micelles. Mol Pharm. 2014;11:1140–50.
Kulhari H, Pooja D, Kota R, Reddy TS, Tabor RF, Shukla R, et al. Cyclic RGDfK peptide functionalized polymeric nanocarriers for targeting gemcitabine to ovarian cancer cells. Mol Pharm. 2016;13:1491–500.
Ji T, Lang J, Wang J, Cai R, Zhang Y, Qi F, et al. Designing liposomes to suppress extracellular matrix expression to enhance drug penetration and pancreatic tumor therapy. ACS Nano. 2017;11:8668–78.
Deshpande S, Spoelstra WK, van Doorn M, Kerssemakers J, Dekker C. Mechanical division of cell-sized liposomes. ACS Nano. 2018;12:2560–8.
Gulati M, Grover M, Singh S, Singh M. Lipophilic drug derivatives in liposomes. Int J Pharm. 1998;165:129–68.
Moog R, Burger AM, Brandl M, Schuler J, Schubert R, Unger C, 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.
Tokunaga Y, Iwasa T, Fujisaki J, Sawai S, Kagayama A. Liposomal sustained-release delivery systems for intravenous injection. IV. Antitumor activity of newly synthesized lipophilic 1-beta-D-arabinofuranosylcytosine prodrug-bearing liposomes. Chem Pharm Bull. 1988;36:3574–83.
Rubas W, Supersaxo A, Weder HG, Hartmann HR, Hengartner H, Schott H, et al. Treatment of murine L1210 lymphoid leukemia and melanoma B16 with lipophilic cytosine arabinoside prodrugs incorporated into unilamellar liposomes. Int J Cancer. 1986;37:149–54.
Sata N, Klonowski-Stumpe H, Han B, Haussinger D, Niederau C. Cytotoxicity of peroxynitrite in rat pancreatic acinar AR4-2J cells. Pancreas. 1997;15:278–84.
Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer. 2007;7:645–58.
Arranz A, Ripoll J. Advances in optical imaging for pharmacological studies. Front Pharmacol. 2015;6:189.
Allen TM, Newman MS, Woodle MC, Mayhew E, Uster PS. Pharmacokinetics and anti-tumor activity of vincristine encapsulated in sterically stabilized liposomes. Int J Cancer. 1995;62:199–204.
We acknowledge the financial support of the Science & Technology Department of Sichuan Province (No. 2018SZ0012, No. 2019YJ0372), the Collaborative Innovation Center of Sichuan for Elderly Care and Health (No. YLZBZ1808), and Chengdu Medical College (No. CYZ17-07).
The authors declare no competing interests.