Director: Julia Y. Ljubimova, MD, PhD
Faculty members: Eggehard Holler PhD, Professor, Satoshi Inoue MD, PhD, Assistant Professor, Hui Ding PhD, Assistant Professor
The Nanomedicine Research Center at the Department of Neurosurgery was established in August, 2011. The purpose is to create and bring to the clinical practice new generation of nanomedicine imaging agents and drugs which are cancer specific for precise diagnostic and highly anti-cancer effective. The nanodrugs will be biodegradable and non-toxic for patients with ability to deliver the multiple anti-tumor inhibitors at the same time directly to cancer cells, overcome the drug resistance, and improve the efficacy of treatment and quality of cancer patients life. Furthermore, the engineered drugs will be useful for each cancer patient with adjustment for individual tumor genome/proteome profile for treatment of primary tumors and in the future for the patient’s tumor progression.
The Nanomedicine Research Center at Cedars-Sinai is part of the NIH/NCI Alliance for Nanotechnology in Cancer 2010-2015, which engages the nation’s leading nanomedicine centers in a collaborative effort aimed at accelerating use of nanotechnology to advance cancer diagnosis, treatment and prevention.
Nanomedicine research involves collaboration not only with partners at other institutions but also across a number of clinical departments at Cedars-Sinai, including surgery, medicine, imaging, pathology, obstetrics and gynecology, and biomedical sciences.
Funding for this research includes a significant level of peer-reviewed grants support from the National Institutes of Health/National Cancer Institute.
Researchers in the Nanomedicine Research Center are led by physician-scientists in the Department of Neurosurgery, focusing on primary brain cancers—including brain gliomas that have a very poor prognosis, and primary HER2-positive and triple negative breast cancers that are largely incurable with current therapy. The program also targets primary lung cancers and brain metastasis from tumors of the lung, breast and other organs. Compared to chemotherapy, the new nanodrugs from PolycefinTM family developed at Nanomedicine Research Center are more effective to treat primary and secondary tumors, increases the maximum dose that can be used, decreases toxicity and immunogenicity, and enhances the ability to target cancer cells specifically. Using the new delivery method allows anti-cancer agents to accumulate directly in solid tumors, which can aid in fighting multi-drug resistant cells.
Summary of PolycefinTM drug family:
- The drug was engineered on a natural biodegradable nanoplatform.
- The drug is specifically delivered crossing multiple bio-barriers such as blood brain barrier/blood tumor barrier (BBB/BTB), and then cancer cell membrane to deliver the anti-cancer drug to the cytoplasm/nuclei of the tumor cells using a targeting monoclonal antibody or peptides.
- This controllable unique drug releases tumor growth inhibiting agents specifically into cancer cells without affecting normal surrounding cells. Minimal toxicity was demonstrated for nanodrug tumor-delivery for Temozolomide, Pt-drugs, and Doxorubicin.
- The active drug component blocks several cancer-specific tumor markers at the same time for multiple tumors: wild/mutated EGFR, Her2/neu, extracellular marker protein, laminin 411.
- There is a significant survival increase in tumor-bearing animals (preclinical data) after the drug administration.
- Using this technology, it is possible to block a combination of several unique markers for each individual patient at the same time, providing a synergistic effect.
Discovery of the new cancer biomarker, laminin 411:
Institute researchers used leading-edge, gene-chip analysis to discover a new cancer biomarker: laminin-411 (formerly known as laminin-8). Human gliomas and invasive breast cancer excessively produce laminin-411, which plays an important role in the ability of tumor cells to spread and grow (Cancer Res. 2001, 61:5601-5610, Breast Cancer Res. 2005, 7:411-421). This biomarker was later analyzed in a number of human gliomas and showed a significant correlation with glial tumor grade, time to recurrence and patients' survival times (Cancer, 2004 101:604-612, Front Biosci. 2006, 11:81-88). Inhibition of this marker and drug delivery into the brain in vivo was developed and glioma tumor reduction was achieved (PNAS USA, 2010, 107:18143-18148)
This test is being used to evaluate the biological behavior of gliomas in order to better plan individualized therapeutic treatment and follow-up regimens for each patient. Clinical trial is ongoing in the Departments of Neurosurgery and Pathology at CSMC for laminin-411 as a glial tumor biomarker (about 300 patients were evaluated).
Production and characterization of polymalic acid – the backbone of Polycefin
1. Fischer H, Erdmann S, Holler E. (1989) An unusual polyanion from Physarum polycephalum that inhibits homologous DNA polymerase-a in vitro. Biochemistry, 28:5219-5226.
2. Holler E, Angerer B, Achhammer G, Miller S, Windisch C. (1992) Biological and biosynthetic properties of poly-L-malate. FEMS Microbiol Revs, 103:109-118.
3. Schmidt A, Windisch C, Holler E. (1995) Nuclear accumulation and homeostasis of the unusual polymer β-poly(L-malate) in plasmodia of Physarum polycephalum. Eur J Cell Biol, 70:373-380.
4. Holler E. (1996) Poly(malic acid) from natural sources, in: Handbook of Engineering Polymeric Materials (Cheremisinoff, N. P., Ed.), pp. 93-103. Marcel Dekker, New York.
5. Gasslmaier B, Holler E. (1997) Specificity and direction of depolymerization of -poly(L-malate) catalysed by polymalatase from Physarum polycephalum. Fluorescence labeling at the carboxy-terminus of β-poly(L-malate). Eur J Biochem, 250:308-314.
6. Lee BS, Holler E. (1999) Fermentation von Kohlehydraten und CO2 zu Polymalat, einem chemisch derivatisierbaren Biopolyanion, in: Biokonversion nachwachsender Rohstoffe/Fachagentur Nachwachsende Rohstoffe e.V., Ed.). Münster: Landwirstschaftsverlag, 46-57.
7. Gasslmaier B, Holler E. (1999) Terminale und andere regiospezifische chemische Derivatisierungen von Polymalat, in: Biokonversion nachwachsender Rohstoffe (Fachagentur Nachwachsende Rohstoffe e.V. Ed.), Münster, Germany: Landwirtschaftsverlag GmbH, 193-198.
8. Lee BS, Holler E. (1999) Effects of culture conditions on β-poly(L-malate) production by Physarum polycephalum. Appl Microbiol Biotechnol, 51:647-652.
9. Lee BS, Holler E. (2000) β-Poly(L-malate) production by non-growing microplasmodia of Physarum polycephalum. Effects of metabolic intermediates and inhibitors. FEMS Microbiol Letters, 193:69-75.
10. Lee BS, Vert M, Holler E. (2002) Water-soluble aliphatic polyesters: poly(malic acid)s, in Biopolymers, Vol. 3a ( Doi Y, Steinbüchel A, Eds). Weinheim (Bergstrasse): Wiley VCH, 75-103.
11. Fernandez CE, Mancera M, Holler E, Bou JJ, Galbis JA, Munoz-Guerra S. (2005) Low molecular weight poly(β-methyl-β,L-malate) of microbial origin: synthesis and crystallization. Macromol Biosci, 5:172-176.
12. Portilla-Arias JA, Garcia-Alvarez M, de Ilarduya AM, Holler E, Munoz-Guerra S. (2006) Nanostructurated complexes of poly(β-L-malate) and cationic surfactants: synthesis, characterization and structural aspects. Biomacromolecules, 7:161-170.
13. Portilla-Arias JA, Montserrat G, Garcıa-Alvarez Martınez de Ilarduya M, Holler E, Munoz-Guerra S. (2006) Thermal decomposition of fungal poly(β,L-malic acid) and poly(β,L-malate)s. Biomacromolecules, 7:3283-3290.
14. Mueller W, Haindl M, Holler E. (2008) Physarum polymalic acid hydrolase Recombinant expression and enzyme activation. Biochem Biophys Res Comun, 377:735-40.
15. Lanz-Landazuri A,Garcia-Alvarez M, Portilla-Arias J, de Ilarduya AM, Patil R, Holler E, Ljubimova JY, Munoz-Guerra S (2011) Nanoparticles formation and encapsulation of antiglioma drugs using poly(methyl malate). Macromol Biosci, 11:1370-1377. A new formulation to acquire encapsulation of chemotherapeutics in polymalic acid particles, which can be further developed on the basis of spherical particles as an alternative to nanopolymer Polycefin formulation
New cancer biomarker, laminin-411 (formerly, laminin 8)
16. Ljubimova JY, Khazenzon NM, Chen Z, Neyman YI, Turner L, Riedinger MS, Black KL. (2001) Analysis of differentially expressed genes in human glial tumors identified by gene array. Int J Oncol, 18:287-297. First demonstration of structural change in malignant brain microvessels. “Malignant” laminin 8 (now laminin-411) in tumors replaces “normal” laminin 9 (now laminin-421) in normal vessels
17. Ljubimova JY Lakhter A, Loksh A,Yong WH, Riedinger MS, Miner JH, Sorokin ML, Ljubimov AV, Black KL. (2001) Overexpression of 4 chain-containing laminins in human glial tumors identified by gene microarray analysis. Cancer Res, 61:5601-5610.
18. Khazenzon NM, Ljubimov AV, Lakhter AJ, Fujiwara H, Sekiguchi K, Sorokin LM, Virtanen I, Black KL, Ljubimova JY. (2003) Antisense inhibition of laminin-8 expression reduces invasion of human gliomas in vitro. Mol Cancer Ther, 2:985-994.
19. Ljubimova JY, Fugita M, Khazenzon NM, Das A, Pikul BB, Newman D, Sekiguchi K, Sorokin LM, Sasaki T, Black KL. (2004) Association between laminin-8 and glial tumor grade, recurrence, and patient survival. Cancer, 101:604-612.
20. Fujita M, Khazenzon NM, Bose S, Sekiguchi K, Sasaki T, Carter WG, Ljubimov AV, Black KL, Ljubimova JY. (2005) Overexpression of β1 chain-containing laminins in capillary basement membranes of human breast cancer and its metastases. Breast Cancer Res, 7:411-421. First demonstration of shifts of vascular laminin isoforms in malignant breast tumors and metastases, similar to brain tumors
21. Ljubimova YL, Fujita M, Khazenzon NM, Ljubimov AV, Black KL. (2006) Changes in laminin isoforms associated with brain tumor invasion and angiogenesis. Front Biosci, 11:81-88.
Polycefin studies in vitro and in vivo.
22. Lee BS, Fujita M, Khazenzon NM, Wawrowsky KA, Wachsmann-Hogiu S, Farkas DL, Black KL, Ljubimova JY, Holler E. (2006) Polycefin, a new prototype of a multifunctional nanoconjugate based on poly(-L-malic acid) for drug delivery. Bioconjug Chem, 17:317-326. First report of Polycefin anti-cancer drug to treat brain cancer
23. Ljubimova JY, Fujita M, Lee BS, Khazenzon NM, Wachsmann-Hogiu S, Farkas DL, Black KL, Holler E. (2006) Nanoconjugates of poly(malic acid) with functional modules for drug delivery. NSTI-Nanotech, 2:354-357.
24. Fujita M, Khazenzon NM, Ljubimov AV, Lee BS, Virtanen I, Holler E, Black KL, Ljubimova JY. (2006) Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis. Angiogenesis, 9:183-191. First report about Polycefin anti-angiogenic effect in vivo
25. Fujita M, Khazenzon NM, Lee B-S, Holler E, Black KL, Ljubimova JY. (2007) Development of nanoconjugate with different monoclonal antibodies to inhibit molecular targets important for tumor angiogenesis. Chapter 9: Cancer Diagnostics, Imaging & Treatment. NSTI-Nanotech, 2:760-762.
26. Fujita M, Lee B-S, Khazenzon NM, Wawrowsky KA, Penichet M, Patil R, Ding H, Holler E, Black KL, Ljubimova JY. (2007) Brain tumor tandem targeting using a combination of monoclonal antibodies attached to biopoly(β-L-malic acid). J Control Release, 122:356-363. New technology for covalent attachment of two different monoclonal antibodies to polymalic acid nanoplatform. Evaluation of functional and therapeutic activity of the attached antibodies
27. Hwang JY, Moffatt-Blue C, Equils O, Fujita M, Jeong J, Khazenzon NM, Lindsley E, Ljubimova JY, Nowatzyk AG, Farkas DL, Wachsmann-Hogiu S. (2007) Multimode optical imaging of small animals: development and applications. Proc Soc Photo-Opt Ins, 6441:644105.
28. Ljubimova JY, Fujita M, Khazenzon NM, Lee BS, Wachsmann-Hogiu S, Farkas DL, BlackKL, Holler E. (2008) Nanoconjugate based on polymalic acid for tumor targeting. Chem Biol Interact, 171:195-203.
29. Dobrovolskaia MA, Neun BW, Clogston JD, Hui Ding H, Ljubimova JY, McNeil SE. (2010) Ambiguities in applying traditional LAL tests to quantify endotoxin in nanoparticle formulations. Nanomed (Lond), 4:555-562.
30. Portilla-Arias J, Patil R, Hu J, Ding H, Black KL, García-Alvarez M, Muñoz-Guerra S, Ljubimova JY, Holler E. (2010) Nanoconjugate platforms development based in poly(β,L-malic acid) methyl esters for tumor drug delivery. J Nanotech, v. 2010, Article ID 825363, 8 pages.
31. Patil R, Portilla-Arias J, Ding H, Inoue S, Konda B, Hu J, Wawrowsky KA, Shin PK, Black KL, Holler E, Ljubimova JY. (2010) Temozolomide delivery to tumor cells by a multifunctional nano vehicle based on poly(β-L-malic acid). Pharm Res, 27:2317-2329. Anti-brain tumor drug Temozolomide acquires longer half-life and increased activity when conjugated with Poilycefin nanoplatform
32. Ding H, Inoue S, Ljubimov AV, Patil R, Portilla-Arias J, Hu J, Konda B, Wawrowsky KA, Fujita M, Karabalin N, Black KL, Holler E, Ljubimova JY. (2010) Inhibition of brain tumor growth by intravenous poly(-L-malic acid) nanobioconjugate with pH-dependent drug release. Proc Natl Acad Sci USA, 107:18143-18148. The paper describes the new mechanism for pH-dependent endosomal drug releasing unit, a novel trileucine tripeptide. It enhances Polycefin anti-cancer drug efficacy in suppressing tumor vessel development and reducing brain tumor growth. This paper was highlighted in Nature Drug Review.
33. Inoue S, Ding H, Portilla-Arias J, Hu J, Konda B, Fujita M, Espinoza A, Suhane S, Riley M, Gates M, Patil R, Penichet ML, Ljubimov AV, Black KL, Holler E, Ljubimova JY. (2011) Polymalic acid-based nanobioconjugate provides efficient systemic breast cancer treatment by inhibiting both HER2/neu receptor synthesis and activity. Cancer Res, 71:1454-1464. Polycefin drug development to treat HER2-positive breast cancer. Treatment effect was superior when compared with FDA-approved drug Trastuzumab
34. Ding H, Portilla-Arias J, Patil R, Black KL, Ljubimova JY, Holler E. (2011) Polymalic acid peptide copolymers: design and optimization for endosomolytic drug delivery. Biomaterials, 32:5269-5278. First characterization of polymalic acid-amino acid copolymers for membrane disruption activity. Investigation of structure-function relations, pH-dependence, toxicity
35. Huang ZW, V Laurent, G Chetouani, Ljubimova JY, Holler E, Loyer TP, Cammas-Marion S. (2012) New functional degradable and bio-compatible nanoparticles based on poly(malic acid) derivatives for site-specific anti-cancer drug delivery. Int J Pharm, 423:84-92.
36. Inoue S, Patil R, Portilla-Arias J, Ding H, Konda B, Espinoza A, Mongayt D, Markman JL, Elramsisy A, Phillips HW, Black KL, Holler E, Ljubimova JY. (2012) Nanobiopolymer for direct targeting and inhibition of EGFR expression in triple negative breast cancer. PLoS One, 7:e31070. Polycefin drug development to efficiently treat EGFR-positive triple negative breast cancer.
37. Daniels TR, Bernabeu E, Rodríguez JA, Patel S, Kozman M, Chiappetta DA, Holler E, Ljubimova JY, Helguera G, Penichet ML. (2012) Transferrin receptors and the targeted delivery of therapeutic agents against cancer. Biochim Biophys Acta, 1820:291–317. Review on using transferrin receptors for getting nanodrugs directly to tumors
38. Hwang JY, Wachsmann-Hogiu S, Ramanujan VK, Ljubimova JY, Gross Z, Gray HB, Medina-Kauwe LK, Farkas DL. (2012) A multimode optical imaging system for preclinical applications in vivo: technology development, multiscale imaging and chemotherapy assessment. Mol Imaging Biol, in press.
39. Ding H, Portilla-Ariasa J, Patil R, Black KL, Ljubimova JY, Holler E. (2013) Distinct mechanisms of membrane permeation induced by two polymalic acid copolymers. Biomaterials 34, 217-225.
40. R. Patil, J. Portilla-Arias, H. Ding, B. Konda, A. Rekechenetskiy, S. Inoue, K. L. Black, E. Holler and J. Y. Ljubimova. (2012) Cellular Delivery of Doxorubicin via pH-Controlled Hydrazone Linkage Using Multifunctional Nano Vehicle Based on Poly(β-L-malic Acid). ). Int. J. Mol. Sci. 2012, 13, 11681-11693.
41. Lanz-Landázuri A, García-Alvarez M, Portilla-Arias J, Martínez de Ilarduya A, Holler E, Ljubimova J, Muñoz-Guerra S. Modifi cation of Microbial Polymalic Acid With Hydrophobic Amino Acids for Drug-Releasing Nanoparticles. Macromol. Chem. Phys. 2012, 213, 1623−1631
42. Ljubimova JU, Holler E. (2012) Biocompatible nanopolymers: the next generation of breast cancer treatment? Nanomed (Lond) in press.