Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Anti-Tumour Activity of Glycodendrimer Nanoparticles in a Subcutaneous MEC-1 Xenograft Model of Human Chronic Lymphocytic Leukemia

Author(s): Barbara Ziemba, Hanna Sikorska, Magdalena Jander, Wojciech Kuncman, Marian Danilewicz, Dietmar Appelhans, Maria Bryszewska, Maciej Borowiec and Ida Franiak-Pietryga*

Volume 20 , Issue 3 , 2020

Page: [325 - 334] Pages: 10

DOI: 10.2174/1871520619666191019093558

Price: $65


Background: Chronic Lymphocytic Leukaemia (CLL) is an indolent disorder, which mainly affects older adults. Since the advent of chemoimmunotherapy, great progress has been made in its treatment. However, some patients develop a more aggressive form of the disease and are included in the group of high-risk CLL patients with a dismal prognosis and a need for new therapies.

Objective: Maltotriose-modified poly(propylene imine) dendrimers were presented as potential agents in targeted therapy for CLL in the murine xenograft model.

Methods: Tumour, brain and internal organs resected from NOD scid gamma mice were subjected to gross and histopathological evaluation.

Results: The results of ex vivo tissue examination indicated that open-shell glycodendrimers prevented/inhibited the spread of CLL into the brain and internal organs and its transformation into a more aggressive form.

Conclusion: The results of the study have a potentially important impact on the design of future personalized therapies as well as clinical trials.

Keywords: Poly(propylene imine), dendrimer, tumour, chronic lymphocytic leukaemia, anticancer therapy, in vivo, ex vivo.

Graphical Abstract
Shaikh, F.; Janjua, A.; Van Gestel, F.; Ahmad, A. Richter transformation of chronic lymphocytic leukemia: A review of fluorodeoxyglucose positron emission tomography-computed tomography and molecular diagnostics. Cureus, 2017, 9(1) e968
[] [PMID: 28191372]
Hallek, M. Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. Am. J. Hematol., 2015, 90(5), 446-460.
[] [PMID: 25908509]
Dreger, P.; Schetelig, J.; Andersen, N.; Corradini, P.; van Gelder, M.; Gribben, J.; Kimby, E.; Michallet, M.; Moreno, C.; Stilgenbauer, S.; Montserrat, E. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood, 2014, 124(26), 3841-3849.
[] [PMID: 25301705]
Dreger, P.; Corradini, P.; Kimby, E.; Michallet, M.; Milligan, D.; Schetelig, J.; Wiktor-Jedrzejczak, W.; Niederwieser, D.; Hallek, M.; Montserrat, E. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: The EBMT transplant consensus. Leukemia, 2007, 21(1), 12-17.
[] [PMID: 17109028]
Smolej, L. Therapeutic approach to patients with chronic lymphocytic leukemia and significant comorbid conditions. Curr. Cancer Drug Targets, 2016, 16(8), 710-720.
[] [PMID: 27055578]
Chen, G.; Emens, L.A. Chemoimmunotherapy: Reengineering tumor immunity. Cancer Immunol. Immunother., 2013, 62(2), 203-216.
[] [PMID: 23389507]
Brown, J.R.; Hallek, M.J.; Pagel, J.M. Chemoimmunotherapy versus targeted treatment in chronic lymphocytic leukemia: When, how long, how much, and in which combination? Am. Soc. Clin. Oncol. Educ. Book, 2016, 35, e387-e398.
[] [PMID: 27249745]
Pettijohn, E.M.; Ma, S. Targeted therapy in Chronic Lymphocytic Leukemia (CLL). Curr. Hematol. Malig. Rep., 2017, 12(1), 20-28.
[] [PMID: 28155013]
Byrd, J.C.; Furman, R.R.; Coutre, S.E.; Burger, J.A.; Blum, K.A.; Coleman, M.; Wierda, W.G.; Jones, J.A.; Zhao, W.; Heerema, N.A.; Johnson, A.J.; Shaw, Y.; Bilotti, E.; Zhou, C.; James, D.F.; O’Brien, S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood, 2015, 125(16), 2497-2506.
[] [PMID: 25700432]
Ramanathan, S.; Jin, F.; Sharma, S.; Kearney, B.P. Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib. Clin. Pharmacokinet., 2016, 55(1), 33-45.
[] [PMID: 26242379]
Jacobson, C.A.; Ritz, J. Time to put the CAR-T before the horse. Blood, 2011, 118(18), 4761-4762.
[] [PMID: 22053170]
Burger, J.A.; O’Brien, S. Evolution of CLL treatment - from chemoimmunotherapy to targeted and individualized therapy. Nat. Rev. Clin. Oncol., 2018, 15(8), 510-527.
[] [PMID: 29777163]
Tsimberidou, A-M. Targeted therapy in cancer. Cancer Chemother. Pharmacol., 2015, 76(6), 1113-1132.
[] [PMID: 26391154]
Taghavi Pourianazar, N.; Mutlu, P.; Gunduz, U. Bioapplications of Poly(Amidoamine) (PAMAM) dendrimers in nanomedicine. J. Nanopart. Res., 2014, 16(4), 2342.
Khan, I.; Saeed, K.; Khan, I. Nanoparticles: Properties, applications and toxicities. Arab. J. Chem., 2017, 12(7), 908-931.
Maly, J.; Pedziwiatr-Werbicka, E.; Maly, M.; Semeradtova, A.; Appelhans, D.; Danani, A.; Zaborski, M.; Klajnert, B.; Bryszewska, M. Highly organized self-assembled dendriplexes based on poly(propylene imine) glycodendrimer and anti-HIV oligodeoxynucleotides. Curr. Med. Chem., 2012, 19(27), 4708-4719.
[] [PMID: 22834818]
Klementieva, O.; Aso, E.; Filippini, D.; Benseny-Cases, N.; Carmona, M.; Juvés, S.; Appelhans, D.; Cladera, J.; Ferrer, I. Effect of poly(propylene imine) glycodendrimers on β-amyloid aggregation in vitro and in APP/PS1 transgenic mice, as a model of brain amyloid deposition and Alzheimer’s disease. Biomacromolecules, 2013, 14(10), 3570-3580.
[] [PMID: 24004423]
Gorzkiewicz, M.; Klajnert-Maculewicz, B. Dendrimers as nanocarriers for nucleoside analogues. Eur. J. Pharm. Biopharm., 2017, 114, 43-56.
[] [PMID: 28089915]
Szulc, A.; Pulaski, L.; Appelhans, D.; Voit, B.; Klajnert-Maculewicz, B. Sugar-modified poly(propylene imine) dendrimers as drug delivery agents for cytarabine to overcome drug resistance. Int. J. Pharm., 2016, 513(1-2), 572-583.
[] [PMID: 27667754]
Szulc, A.; Signorelli, M.; Schiraldi, A.; Appelhans, D.; Voit, B.; Bryszewska, M.; Klajnert-Maculewicz, B.; Fessas, D. Maltose modified poly(propylene imine) dendrimers as potential carriers of nucleoside analog 5′-triphosphates. Int. J. Pharm., 2015, 495(2), 940-947.
[] [PMID: 26456295]
Ziemba, B.; Franiak-Pietryga, I.; Pion, M.; Appelhans, D.; Muñoz-Fernández, M.Á.; Voit, B.; Bryszewska, M.; Klajnert-Maculewicz, B. Toxicity and proapoptotic activity of poly(propylene imine) glycodendrimers in vitro: Considering their contrary potential as biocompatible entity and drug molecule in cancer. Int. J. Pharm., 2014, 461(1-2), 391-402.
[] [PMID: 24361266]
Franiak-Pietryga, I.; Maciejewski, H.; Ostrowska, K.; Appelhans, D.; Voit, B.; Misiewicz, M.; Kowalczyk, P.; Bryszewska, M.; Borowiec, M. Dendrimer-based nanoparticles for potential personalized therapy in chronic lymphocytic leukemia: Targeting the BCR-signaling pathway. Int. J. Biol. Macromol., 2016, 88, 156-161.
[] [PMID: 26987432]
Franiak-Pietryga, I.; Maciejewski, H.; Ziemba, B.; Appelhans, D.; Voit, B.; Robak, T.; Jander, M.; Treliński, J.; Bryszewska, M.; Borowiec, M. Blockage of Wnt/β-Catenin signaling by nanoparticles reduces survival and proliferation of CLL cells in vitro-preliminary study. Macromol. Biosci., 2017, 17(11)
[] [PMID: 28762636]
Franiak-Pietryga, I.; Ostrowska, K.; Maciejewski, H.; Appelhans, D.; Misiewicz, M.; Ziemba, B.; Bednarek, M.; Bryszewska, M.; Borowiec, M. PPI-G4 glycodendrimers upregulate TRAIL-Induced apoptosis in chronic lymphocytic leukemia cells. Macromol. Biosci., 2017, 17(5) 1600169
[] [PMID: 27996200]
Franiak-Pietryga, I.; Ostrowska, K.; Maciejewski, H.; Ziemba, B.; Appelhans, D.; Voit, B.; Jander, M.; Treliński, J.; Bryszewska, M.; Borowiec, M. Affecting NF-κB cell signaling pathway in chronic lymphocytic leukemia by dendrimers-based nanoparticles. Toxicol. Appl. Pharmacol., 2018, 357, 33-38.
[] [PMID: 30125597]
Franiak-Pietryga, I.; Ziółkowska, E.; Ziemba, B.; Appelhans, D.; Maciejewski, H.; Voit, B.; Kaczmarek, A.; Robak, T.; Klajnert-Maculewicz, B.; Cebula-Obrzut, B.; Smolewski, P.; Borowiec, M.; Bryszewska, M. Glycodendrimer PPI as a potential drug in chronic lymphocytic leukaemia. The influence of glycodendrimer on apoptosis in in vitro B-CLL cells defined by microarrays. Anticancer. Agents Med. Chem., 2017, 17(1), 102-114.
[PMID: 27349446]
Franiak-Pietryga, I.; Ziółkowska, E.; Ziemba, B.; Appelhans, D.; Voit, B.; Szewczyk, M.; Góra-Tybor, J.; Robak, T.; Klajnert, B.; Bryszewska, M. The influence of maltotriose-modified poly(propylene imine) dendrimers on the chronic lymphocytic leukemia cells in vitro: Dense shell G4 PPI. Mol. Pharm., 2013, 10(6), 2490-2501.
[] [PMID: 23641871]
Ziemba, B. In vivo toxicity of poly(propyleneimine) dendrimers. J. Biomed. Mater. Res. - Part A, 2011, 99(2), 261-268.
[] [PMID: 21976451]
Ziemba, B.; Matuszko, G.; Appelhans, D.; Voit, B.; Bryszewska, M.; Klajnert, B. Genotoxicity of poly(propylene imine) dendrimers. Biopolymers, 2012, 97(8), 642-648.
[] [PMID: 22605555]
Ziemba, B.; Halets, I.; Shcharbin, D.; Appelhans, D.; Voit, B.; Pieszynski, I.; Bryszewska, M.; Klajnert, B. Influence of fourth generation poly(propyleneimine) dendrimers on blood cells. J. Biomed. Mater. Res.- Part A, 2012, 100(11), 2870-2880.
Filimon, A.; Sima, L.E.; Appelhans, D.; Voit, B.; Negroiu, G. Internalization and intracellular trafficking of poly(propylene imine) glycodendrimers with maltose shell in melanoma cells. Curr. Med. Chem., 2012, 19(29), 4955-4968.
[] [PMID: 23033945]
Franiak-Pietryga, I.; Ziemba, B.; Messmer, B.; Skowronska-Krawczyk, B. Dendrimers as drug nanocarriers: The future of gene therapy and targeted therapies in cancer. In: Dendrimers - Fundamentals and Applications; IntechOpen: London, 2018; pp. 7-27.
Ziemba, B.; Sikorska, H.; Jander, M.; Appelhans, D.; Bryszewska, M.; Borowiec, M.; Franiak-Pietryga, I. Anti-tumour activity of glycodendrimer nanoparticles in subcutaneous MEC-1 xenograft model of human CLL.Proceedings of the Polish Scientific Networks conferenc; Łódź, Poland, 2018. June, 21-23. Abstract Book; pp 135: Available from:.
Stacchini, A.; Aragno, M.; Vallario, A.; Alfarano, A.; Circosta, P.; Gottardi, D.; Faldella, A.; Rege-Cambrin, G.; Thunberg, U.; Nilsson, K.; Caligaris-Cappio, F. MEC-1 and MEC-2: Two new cell lines derived from B-chronic lymphocytic leukaemia in prolymphocytoid transformation. Leuk. Res., 1999, 23(2), 127-136.
[] [PMID: 10071128]
Appelhans, D.; Oertel, U.; Mazzeo, R.; Komber, H.; Hoffmann, J.; Weidner, S.; Brutschy, B.; Voit, B.; Ottaviani, M.F. Dense-Shell glycodendrimers: UV/Vis and electron paramagnetic resonance study of metal ion complexation. Proc. R. Soc. A, 2010, 466(2117), 1489-1513.
Mkandawire, M.; Pohl, A.; Gubarevich, T.; Lapina, V.; Appelhans, D.; Rödel, G.; Pompe, W.; Schreiber, J.; Opitz, J. Selective targeting of green fluorescent nanodiamond conjugates to mitochondria in HeLa cells. J. Biophotonics, 2009, 2(10), 596-606.
[] [PMID: 19504515]
Andreozzi, E.; Antonelli, A.; Cangiotti, M.; Canonico, B.; Sfara, C.; Pianetti, A.; Bruscolini, F.; Sahre, K.; Appelhans, D.; Papa, S.; Ottaviani, M.F. Interactions of nitroxide-conjugated and non-conjugated glycodendrimers with normal and cancer cells and biocompatibility studies. Bioconjug. Chem., 2017, 28(2), 524-538.
[] [PMID: 28068077]
Loisel, S.; Ster, K.L.; Quintin-Roue, I.; Pers, J-O.; Bordron, A.; Youinou, P.; Berthou, C. Establishment of a novel human B-CLL-like xenograft model in nude mouse. Leuk. Res., 2005, 29(11), 1347-1352.
[] [PMID: 15896841]
Bertilaccio, M.T.S.; Scielzo, C.; Simonetti, G.; Ponzoni, M.; Apollonio, B.; Fazi, C.; Scarfò, L.; Rocchi, M.; Muzio, M.; Caligaris-Cappio, F.; Ghia, P. A novel Rag2-/-gammac-/--xenograft model of human CLL. Blood, 2010, 115(8), 1605-1609.
[] [PMID: 20018917]
Johnson, A.J.; Lucas, D.M.; Muthusamy, N.; Smith, L.L.; Edwards, R.B.; De Lay, M.D.; Croce, C.M.; Grever, M.R.; Byrd, J.C. Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. Blood, 2006, 108(4), 1334-1338.
[] [PMID: 16670263]
Santos, F.P.S.; O’Brien, S. Small lymphocytic lymphoma and chronic lymphocytic leukemia: Are they the same disease? Cancer J., 2012, 18(5), 396-403.
[] [PMID: 23006943]
Strati, P.; Jain, N.; O’Brien, S. Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin. Proc., 2018, 93(5), 651-664.
[] [PMID: 29728204]
Bichi, R.; Shinton, S.A.; Martin, E.S.; Koval, A.; Calin, G.A.; Cesari, R.; Russo, G.; Hardy, R.R.; Croce, C.M. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc. Natl. Acad. Sci. USA, 2002, 99(10), 6955-6960.
[] [PMID: 12011454]
Kojima, K.; Duvvuri, S.; Ruvolo, V.; Samaniego, F.; Younes, A.; Andreeff, M. Decreased sensitivity of 17p-deleted chronic lymphocytic leukemia cells to a small molecule BCL-2 antagonist ABT-737. Cancer, 2012, 118(4), 1023-1031.
[] [PMID: 21761401]
Shultz, L.D.; Goodwin, N.; Ishikawa, F.; Hosur, V.; Lyons, B.L.; Greiner, D.L. Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harb. Protoc., 2014, 2014(7), 694-708.
[] [PMID: 24987146]
Dobrovolskaia, M.A. Dendrimers effects on the immune system: Insights into toxicity and therapeutic utility. Curr. Pharm. Des., 2017, 23(21), 3134-3141.
[] [PMID: 28294045]
Jatczak-Pawlik, I.; Gorzkiewicz, M.; Studzian, M.; Appelhans, D.; Voit, B.; Pulaski, L.; Klajnert-Maculewicz, B. Sugar-modified poly(propylene imine) dendrimers stimulate the NF-κB pathway in a myeloid cell line. Pharm. Res., 2017, 34(1), 136-147.
[] [PMID: 27766462]
Fruchon, S.; Poupot, R.; Fruchon, S.; Poupot, R. The ABP dendrimer, a drug-candidate against inflammatory diseases that triggers the activation of interleukin-10 producing immune cells. Molecules, 2018, 23(6), 1272.
[] [PMID: 29799517]
Caminade, A-M.; Fruchon, S.; Turrin, C-O.; Poupot, M.; Ouali, A.; Maraval, A.; Garzoni, M.; Maly, M.; Furer, V.; Kovalenko, V.; Majoral, J.P.; Pavan, G.M.; Poupot, R. The key role of the scaffold on the efficiency of dendrimer nanodrugs. Nat. Commun., 2015, 6(1), 7722.
[] [PMID: 26169490]
Yee, K.W.L.; O’Brien, S.M. Chronic lymphocytic leukemia: Diagnosis and treatment. Mayo Clin. Proc., 2006, 81(8), 1105-1129.
[] [PMID: 16901035]
Ghia, P.; Bertilaccio, M.T.; Scielzo, C.; Simonetti, G.; Apollonio, B.; Fazi, C.; Muzio, M.; Ponzoni, M.; Caligaris-Cappio, F. Novel mouse models of Chronic Lymphocytic Leukemia (CLL) unravel the molecular mechanisms controlling bone marrow involvement by leukemic B cells. Blood, 2009, 114(22), 360.
Verner, J.; Trbusek, M.; Chovancova, J.; Jaskova, Z.; Moulis, M.; Folber, F.; Halouzka, R.; Mayer, J.; Pospisilova, S.; Doubek, M. NOD/SCID IL2Rγ-null mouse xenograft model of human p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma using permanent cell lines. Leuk. Lymphoma, 2015, 56(11), 3198-3206.
[] [PMID: 25827173]
Rossi, D.; Gaidano, G. Richter syndrome: Molecular insights and clinical perspectives. Hematol. Oncol., 2009, 27(1), 1-10.
[] [PMID: 19206112]
Jain, P.; O’Brien, S. Richter’s transformation in chronic lymphocytic leukemia. Oncology (Williston Park), 2012, 26(12), 1146-1152.
[PMID: 23413591]
Rossi, D.; Spina, V.; Deambrogi, C.; Rasi, S.; Laurenti, L.; Stamatopoulos, K.; Arcaini, L.; Lucioni, M.; Rocque, G.B.; Xu-Monette, Z.Y.; Visco, C.; Chang, J.; Chigrinova, E.; Forconi, F.; Marasca, R.; Besson, C.; Papadaki, T.; Paulli, M.; Larocca, L.M.; Pileri, S.A.; Gattei, V.; Bertoni, F.; Foà, R.; Young, K.H.; Gaidano, G. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood, 2011, 117(12), 3391-3401.
[] [PMID: 21266718]
Jamroziak, K.; Tadmor, T.; Robak, T.; Polliack, A. Richter syndrome in chronic lymphocytic leukemia: updates on biology, clinical features and therapy. Leuk. Lymphoma, 2015, 56(7), 1949-1958.
[] [PMID: 25356923]
Lopes da Silva, R. Spectrum of neurologic complications in chronic lymphocytic leukemia. Clin. Lymphoma Myeloma Leuk., 2012, 12(3), 164-179.
[] [PMID: 22192500]
Strati, P.; Uhm, J.H.; Kaufmann, T.J.; Nabhan, C.; Parikh, S.A.; Hanson, C.A.; Chaffee, K.G.; Call, T.G.; Shanafelt, T.D. Prevalence and characteristics of central nervous system involvement by chronic lymphocytic leukemia. Haematologica, 2016, 101(4), 458-465.
[] [PMID: 26819053]
Beck, E.H.; Amato, A.A.; Greenberg, S.A. Inclusion body myositis and chronic lymphocytic leukemia: a case series. Neurology, 2014, 83(1), 98-99.
[] [PMID: 24857927]
Aversa, Z.; Costelli, P.; Muscaritoli, M. Cancer-induced muscle wasting: Latest findings in prevention and treatment. Ther. Adv. Med. Oncol., 2017, 9(5), 369-382.
[] [PMID: 28529552]
Avramis, V.I.; Plunkett, W. Metabolism and therapeutic efficacy of 9-beta-D-arabinofuranosyl-2-fluoroadenine against murine leukemia P388. Cancer Res., 1982, 42(7), 2587-2591.
[PMID: 7083151]
Scheifele, D.; Bjornson, G.; Dimmick, J. Rapid postmortem gut autolysis in infant rats: a potential problem for investigators. Can. J. Vet. Res., 1987, 51(3), 404-406.
[PMID: 3651898]
Moghimi, S.M.; Wibroe, P.P.; Helvig, S.Y.; Farhangrazi, Z.S.; Hunter, A.C. Genomic perspectives in inter-individual adverse responses following nanomedicine administration: The way forward. Adv. Drug Deliv. Rev., 2012, 64(13), 1385-1393.
[] [PMID: 22634158]
Moghimi, S.M. Nanomedicine safety in preclinical and clinical development: focus on idiosyncratic injection/infusion reactions. Drug Discov. Today, 2018, 23(5), 1034-1042.
[] [PMID: 29146517]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy