Article

Targeted Dendrimer Chemotherapy in an Animal Model for Head and Neck Squamous Cell Carcinoma

Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons (Impact Factor: 1.43). 06/2011; 69(9):2452-9. DOI: 10.1016/j.joms.2010.12.041
Source: PubMed

ABSTRACT

Nanoparticle drug delivery offers a potential solution in the treatment of cancer. Using a heterotopic tumor model for head and neck squamous cell carcinoma (HNSCC), tumors of variable folate binding protein-alpha (FBP-α) have been treated to delineate receptor necessity as well as efficacy and toxicity of folate targeted chemotherapy.
University of Michigan Squamous Cell Carcinoma (UM-SCC) and American Type Culture Collection (ATCC) cell lines were screened using quantitative real-time polymerase chain reaction for FBP-α expression. Acetylated generation 5 dendrimers conjugated to the targeting moiety folic acid and the therapeutic moiety methotrexate were fabricated and administered to severe combined immunodeficiency (SCID) CB-17 mice inoculated with UM-SCC-1, UM-SCC-17B, and UM-SCC-22B cancer cells. Mice were injected with targeted therapy, free methotrexate, or saline control and monitored for drug efficacy and toxicity.
Targeted therapy was effective relative to receptor level expression. Targeted therapy could be delivered in molar doses 3 times that of free drug. The treatment of a high folate expression tumor cell population was noted to have increased efficacy over saline (P < .01) and free methotrexate (P = .03) as well as decreased systemic toxicity.
This report represents the first translation of dendrimer-based chemotherapy to HNSCC and underscores its effectiveness as an antitumor agent in human cancer cell lines with lower levels of FBP-α than the in vitro and in vivo models previously reported.

Download full-text

Full-text

Available from: István J Majoros
  • Source
    • "Chemotherapeutic drugs (eg, paclitaxel, doxorubicin) conjugated with FA have been shown not only to be selectively transported into KB cells,14,15 Bel 7402 cells,16 and nude mice xenograft tumors, but also to achieve better antitumor results. Saba et al detected the FR in 45% of primary squamous cell carcinomas of the head and neck and 40% of corresponding lymph node metastases.13 Ward et al made acetylated generation 5 dendrimers conjugated with FA and methotrexate as the therapeutic moiety in compound reagents and administered them to nude mice with UM-SCC-1, UM-SCC-17B, and UM-SCC-22B cancer xenografts.17 They found this targeted therapy could be delivered in molar doses three times that of the free drug and with lower systemic toxicity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunohistochemistry and an immunofluorescence technique was used to detect folate receptor expression in tissue samples and cell lines of head and neck squamous carcinoma, including 20 tissue samples of nasopharyngeal carcinoma, 16 tissue samples of laryngeal carcinoma, and HNE-1, HNE-2, CNE-1, CNE-2, SUNE-1, 5-8F, and Hep-2 cell lines. Iron staining, electron microscopy, and magnetic resonance imaging were used to observe endocytosis of folate-conjugated cisplatin-loaded magnetic nanoparticles (CDDP-FA-ASA-MNP) in cultured cells and transplanted tumors. As shown by immunohistochemistry, 83.3% (30/36) of the head and neck squamous carcinomas expressed the folate receptor versus none in the control group (0/24). Only the HNE-1 and Hep-2 cell lines expressed the folate receptor, and the other five cell lines did not. Endocytosis of CDDP-FA-ASA-MNP was seen in HNE-1 and Hep-2 cells by iron staining and electron microscopy. A similar result was seen in transplanted tumors in nude mice. Magnetic resonance imaging showed low signal intensity of HNE-1 cells and HNE-1 transplanted tumors on T2-weighted images after uptake of CDDP-FA-ASA-MNP, and this was not seen in CNE-2 transplanted tumors. In conclusion, head and neck squamous carcinoma cell strongly expressed the folate receptor, while normal tissue did not. The folate receptor can mediate endocytosis of folate-conjugated anticancer nanomedicines, and lays the foundation for molecular targeted treatment of cancer.
    Preview · Article · Jul 2013 · International Journal of Nanomedicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nanotechnology, a separate field of knowledge since 1980s, involves utilization of nanomaterials not only in electronics and catalysis, but also in biomedical research including drug delivery, bioimaging, biomedical-diagnostics and tissue engineering. Multidisciplinary of this science has led to the development of different areas of technology and might contribute to innovations that will, as a final consequence, help humanity. Dendrimers are large and complex molecules that are characterized by well-defined nanoscale architecture, monodispersity and structural versatility. These highly interesting polymers consist of three elements: core, branches and peripheral groups. There is a wide variety of potential applications of dendritic polymers. One of the most promising is utilization of polyamidoamine (PAMAM) dendrimers as drug delivery devices. Among pharmaceuticals that have been connected with different types of dendrimers are nonsteroidal anti-inflammatory drugs (NSAIDs), anticancer drugs and other. Dendrimers application as drug carriers improves pharmacokinetic properties of drug particles, decreases drugs' side effects and, by possibility of surface modification with different ligands, enables to target specific tissues and tumor cells. Dendrimers might be also utilized as devices for delivery of genetic material and contrast agents for magnetic resonance imaging (MRI).
    Preview · Article · May 2012 · Nano brief reports and reviews
  • [Show abstract] [Hide abstract]
    ABSTRACT: Current trends in research dealing with methods of developing effective chemotherapy for the two most dangerous killers - breast and colon cancers have been discussed. The input brought by nanotechnology is presented with particular stress on the use of dendrimers. These unique "polymeric compounds" after modification can form intelligent species, transporting drugs into specific areas and at the same time can be used for monitoring the state of organs attacked by cancer cells, as well as the progress of the curing process. They can help to limit the anticancer drugs delivery to designed goals only, eliminating many side effects of chemotherapy. Breast and colon cancer are major problem for public health care in many countries all over the world. During last twenty years a dramatic increase in incidence of both of them has been observed, especially in industrialized countries. Probably, both of them are caused, apart from the hereditary syndromes, by specific point mutation, some hormonal factors in breast cancer and by the strong co-influence of environmental factors and dietary exposure of a patient.
    No preview · Article · Sep 2012 · Current Medicinal Chemistry
Show more