LDL-Receptor Mediated Drug Targeting to Malignant Tumors in the Brain

  • Ranajoy Sarkar
  • David S. Halpern
  • Steven K. Jacobs
  • D. Robert Lu


Malignant tumors are composed of abnormal cells that usually grow very aggressively. It is extremely difficult to treat many of these malignant tumors with conventional methods, including surgical resection, radiation therapy, chemotherapy and combinations of these modalities. To enhance the efficacy of tumor treatment with chemotherapy, targeted drug delivery resulting in high concentrations of therapeutic compounds in tumor cells and relatively low concentrations in neighboring normal cells has been attractive and many approaches for drug targeting have been extensively evaluated.


Cholesteryl Ester Target Drug Delivery Boron Neutron Capture Therapy Intermediate Density Lipoprotein Biomedical Aspect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Danik M, Champagne D, Petit-Turcotte C, Beffert U and Poirier J. Brain lipoprotein metabolism and its relation to neurodegenerative disease. Crit. Rev. Neur. 1999; 13 (4): 357–407Google Scholar
  2. 2.
    Hussain M M, Strickland D K and Bakillah A. The mammalian low-density lipoprotein receptor family. Annu Rev Nutr 1999; 19: 141–172CrossRefGoogle Scholar
  3. 3.
    Murakami M, Ushio Y, Mihara Y, Kuratsu J, Horiuchi S, Morino Y. Cholesterol uptake by human glioma cells via receptor-mediated endocytosis of low-density lipoprotein J Neurosurg 1990 73 (5): 760–767Google Scholar
  4. 4.
    Maletinska L, Blakely EA, Bjornstad KA, Deen DF, Knoff LJ, Forte TM. Human glioblastoma cell lines: levels of low-density lipoprotein receptor and low-density lipoprotein receptor-related protein. Cancer Res 2000; 60 (8): 2300–2303Google Scholar
  5. 5.
    Gueddari N, Favre G, Hachem H, Marek E, Le Gaillard F, Soula G. Evidence for up-regulated low density lipoprotein receptor in human lung adenocarcinoma cell line A549. Biochimie 1993; 75 (9): 811–819CrossRefGoogle Scholar
  6. 6.
    Yen CF, Kalunta CI, Chen FS, Kaptein JS, Lin CK, Lad PM. Regulation of low-density lipoprotein receptors and assessment of their functional role in Burkitt’s lymphoma cells. Biochim Biophys Acta 1995; 1257 (1): 47–57CrossRefGoogle Scholar
  7. 7.
    Chen Y, Hughes-Fulford M. Human prostate cancer cells lack feedback regulation of low-density lipoprotein receptor and its regulator, SREBP2. Int J Cancer 2001; 91 (1): 41–45CrossRefGoogle Scholar
  8. 8.
    Lombardi P, Norata G, Maggi F M, Canti G, Franco P, Nicolin A and Catapano A L. Assimilation of LDL by experimental tumors in mice. Biochim Biophys Acta 1989; 1003 (3): 301–306CrossRefGoogle Scholar
  9. 9.
    Vitols S, Gahrton G, Bjorkholm M and Peterson C. Hypocholesterolaemia in malignancy due to elevated low-density-lipoprotein-receptor activity in tumor cells: evidence from studies in patients with leukemia. Lancet 1985; 2: 1150–1154CrossRefGoogle Scholar
  10. 10.
    Nakagawa T, Ueyama Y, Nozaki S, Yamashita S, Menju M, Funahashi T, KamedaTakemura K, Kubo M, Tokunaga K, Tanaka T, et al. Marked hypocholesterolemia in a case with adrenal adenoma-enhanced catabolism of low density lipoprotein (LDL) via the LDL receptors of tumor cells. J Clin Endocrinol Metab 1995; 80 (1): 92–96CrossRefGoogle Scholar
  11. 11.
    Meresse S, Delbart C, Fruchart JC, Cecchelli R. Low-density lipoprotein receptor on endothelium of brain capillaries. J Neurochem 1989; 53 (2): 340–345CrossRefGoogle Scholar
  12. 12.
    Lucarelli M, Gennarelli M, Cardelli P, Novelli G, Scarpa S, Dallapiccola B and Strom R. Expression of receptors for native and chemically modified low-density lipoproteins in brain microvessels,. FEBS Letters 1997; 401 (1): 53–58CrossRefGoogle Scholar
  13. 13.
    Dehouck B, Fenart, L, Dehouck M, Pierce A, Torpier G and Cecchelli R. A new function for the LDL receptor: transcytosis of LDL across the Blood Brain Barrier. J Cell Biol 1997; 138 (4): 877–889CrossRefGoogle Scholar
  14. 14.
    Gutman RL, Peacock G. Lu D.R. Targeted drug delivery for brain cancer treatment. J. Controlled Release, 2000; 65: 31–41.CrossRefGoogle Scholar
  15. 15.
    Lu DR and Ji B. Carborane containing cholesterol, a new type of molecule for targeted boron drug delivery. U.S. Patent No. 09 /609, 957, (2001)Google Scholar
  16. 16.
    Feakes DA, Spinler JK and Harris FR. Synthesis of Boron containing cholesterol derivatives for incorporation into unilamellar liposomes and evaluation as potential agents for BNCT. Tetrahedron 1999; 55: 11177–11186CrossRefGoogle Scholar
  17. 17.
    Chen W, Mehta S and Lu DR. Selective boron drug delivery to brain tumors for boron neutron capture therapy. Adv. Drug Delivery Reviews 1997; 26: 231–247.CrossRefGoogle Scholar
  18. 18.
    Shawer M, Greenspan P, Q ie S and Lu DR. VLDL-resembling phospholipidsubmicron emulsion for cholesterol-based drug targeting. J. Pharm. Sci. 2002 (In press)Google Scholar
  19. 19.
    Ji B, Chen W, Halpern DS and Lu DR. Cell culture and animal studies for intracerebral delivery of borocaptate in liposomal formulation. Drug Delivery 2001; 8: 13–17CrossRefGoogle Scholar
  20. 20.
    Lundberg S. Preparation of drug-low density lipoprotein complexes for delivery of antitumoral drugs via the low density lipoprotein pathway. Cancer Res 1987; 47: 4105–4108Google Scholar
  21. 21.
    Lestavel-Delattre S, Martin-Nizard F, Clayey V, Testard P, Favre G, Doualin G et. al. Low Density Lipoprotein for delivery of an acrylophenone antineoplastic molecule into malignant cells. Cancer Res 1992; 52: 3629–3635Google Scholar
  22. 22.
    Kerr D J, Hynds S A, Shepherd J, Packard C J and Kaye S B. Comparative cellular uptake and cytotoxicity of a complex of daunomycin-low density lipoprotein in human squamous lung tumor cell monolayer. Biochem Pharmacol 1988; 37 (20): 3981–3986CrossRefGoogle Scholar
  23. 23.
    Samadi-Baboli M, Favre G, Canal P and Soula G. Low Density Lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice. Br J Cancer 1993; 68 (2): 319–326CrossRefGoogle Scholar
  24. 24.
    Reddi E. Role of delivery vehicles for photosensitizers in the photodynamic therapy of tumors. J Photochem Photobiol B: Biology 1997; 37: 189–195CrossRefGoogle Scholar
  25. 25.
    Reddi E, Zhou C, Biolo R, Menegaldo E and Joni G. Liposome or LDL-administered Zn (II)-phthalocyanine as a photodynamic agent for tumors. I. Pharmacokinetic properties and phototherapeutic efficiency. Br J Cancer 1990; 61: 407–411CrossRefGoogle Scholar
  26. 26.
    Laster B H, Kahl S B, Popenoe E A, Pate D W and Fairchild R G. Biological efficacy of boronated low-density lipoprotein for boron neutron capture therapy as measured in cell culture. Cancer Res 1991; 51: 4588–4593Google Scholar
  27. 27.
    De Smidt P C and van Berkel T J. Prolonged serum half life of antineoplastic drugs by incorporation into the low density lipoprotein. Cancer Res 1990; 50: 7476–7482Google Scholar
  28. 28.
    Vitols S, Soderberg-Reid K, Masquelier M, Sjostrom B and Peterson C. Low density lipoprotein for delivery of a water-insoluble alkylating agent to malignant cells. In vitro and in vivo studies of a drug-lipoprotein complex. Br J Cancer 1990; 62(5): 724729Google Scholar
  29. 29.
    Versluis AJ, Rensen PC, Rump ET, Van Berkel TJ and Bijsterbosch MK. Low-density lipoprotein receptor-mediated delivery of a lipophilic daunorubicin derivative to B16 tumours in mice using apolipoprotein E-enriched liposomes. Br J Cancer 1998; 78 (12): 1607–1614CrossRefGoogle Scholar
  30. 30.
    Vitols S, Angelin B, Ericsson S, Gahrton G, Juliusson G, Masquelier M. Uptake of low-density lipoproteins by human leukemic cells in vivo: relation to plasma lipoprotein levels and possible relevance for selective chemotherapy. Proc Natl Acad Sci USA 1990b; 87: 2598–2602.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Ranajoy Sarkar
    • 1
  • David S. Halpern
    • 2
  • Steven K. Jacobs
    • 3
  • D. Robert Lu
    • 1
  1. 1.College of PharmacyUniversity of GeorgiaAthensUSA
  2. 2.Isotron, Inc.AlpharettaUSA
  3. 3.New York Medical CollegeNew WindsorUSA

Personalised recommendations