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Nanoparticle-mediated p53 gene therapy for tumor inhibition

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Abstract

The p53 tumor suppressor gene is mutated in 50% of human cancers, resulting in more aggressive disease with greater resistance to chemotherapy and radiation therapy. Advances in gene therapy technologies offer a promising approach to restoring p53 function. We have developed polymeric nanoparticles (NPs), based on poly(lactic-co-glycolic acid), that provide sustained intracellular delivery of plasmid DNA, resulting in sustained gene expression without vector-associated toxicity. Our previous studies with p53 gene-loaded NPs (p53NPs) demonstrated sustained antiproliferative effects in cancer cells in vitro. The objective of this study was to evaluate the efficacy of p53NPs in vivo. Tumor xenografts in mice were established with human p53-null prostate cancer cells. Animals were treated with p53NPs by either local (intratumoral injection) or systemic (intravenous) administration. Controls included saline, p53 DNA alone, and control NPs. Mice treated with local injections of p53NPs demonstrated significant tumor inhibition and improved animal survival compared with controls. Tumor inhibition corresponded to sustained and greater p53 gene and protein expression in tumors treated with p53NPs than with p53 DNA alone. A single intravenous dose of p53NPs was successful in reducing tumor growth and improving animal survival, although not to the same extent as with local injections. Imaging studies showed that NPs accumulate in tumor tissue after intravenous injection; however, further improvement in tumor targeting efficiency of p53NPs may be needed for better outcome. In conclusion, the NP-mediated p53 gene therapy is effective in tumor growth inhibition. NPs may be developed as nonviral vectors for cancer and other genetic diseases.

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References

  • Bossi G, Sacchi A. Restoration of wild-type p53 function in human cancer: relevance for tumor therapy. Head Neck. 2007;29(3):272–84.

    Article  PubMed  Google Scholar 

  • Bouvet M, Ellis LM, Nishizaki M, Fujiwara T, Liu W, Bucana CD, et al. Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res. 1998;58(11):2288–92.

    CAS  PubMed  Google Scholar 

  • Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009;9(12):862–73.

    Article  CAS  PubMed  Google Scholar 

  • Carson DA, Lois A. Cancer progression and p53. Lancet. 1995;346(8981):1009–11.

    Article  CAS  PubMed  Google Scholar 

  • Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, Giulini B, et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2009;138(6):1083–95.

    Article  CAS  PubMed  Google Scholar 

  • Cristofanilli M, Krishnamurthy S, Guerra L, Broglio K, Arun B, Booser DJ, et al. A nonreplicating adenoviral vector that contains the wild-type p53 transgene combined with chemotherapy for primary breast cancer: safety, efficacy, and biologic activity of a novel gene therapy approach. Cancer. 2006;107(5):935–44.

    Article  CAS  PubMed  Google Scholar 

  • Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med. 2007;58:267–84.

    Article  CAS  PubMed  Google Scholar 

  • Danhier F, Vroman B, Lecouturier N, Crokart N, Pourcelle V, Freichels H, et al. Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles loaded with paclitaxel. J Control Release. 2009;140(2):166–73.

    Article  CAS  PubMed  Google Scholar 

  • Dings RP, Van Laar ES, Loren M, Webber J, Zhang Y, Waters SJ, et al. Inhibiting tumor growth by targeting tumor vasculature with galectin-1 antagonist anginex conjugated to the cytotoxic acylfulvene, 6-hydroxylpropylacylfulvene. Bioconjug Chem. 2010;21(1):20–7.

    Article  CAS  PubMed  Google Scholar 

  • Ditto AJ, Shah PN, Yun YH. Non-viral gene delivery using nanoparticles. Expert Opin Drug Deliv. 2009;6(11):1149–60.

    Article  CAS  PubMed  Google Scholar 

  • Ecke TH, Schlechte HH, Schiemenz K, Sachs MD, Lenk SV, Rudolph BD, et al. TP53 gene mutations in prostate cancer progression. Anticancer Res. 2010;30(5):1579–86.

    CAS  PubMed  Google Scholar 

  • Foy SP, Manthe RL, Foy ST, Dimitrijevic S, Krishnamurthy N, Labhasetwar V. Optical imaging and magnetic field targeting of magnetic nanoparticles in tumors. ACS Nano. 2010;4(9):5217–24.

    Article  CAS  PubMed  Google Scholar 

  • Heilbronn R, Weger S. Viral vectors for gene transfer: current status of gene therapeutics. Handb Exp Pharmacol. 2010;197:143–70.

    Article  CAS  PubMed  Google Scholar 

  • Hirshfield KM, Rebbeck TR, Levine AJ. Germline mutations and polymorphisms in the origins of cancers in women. J Oncol. 2010;2010:297671.

    PubMed  Google Scholar 

  • Jerry DJ, Tao L, Yan H. Regulation of cancer stem cells by p53. Breast Cancer Res. 2008;10(4):304.

    Article  PubMed  Google Scholar 

  • Labhasetwar V, Bonadio J, Goldstein S, Chen W, Levy RJ. A DNA controlled-release coating for gene transfer: transfection in skeletal and cardiac muscle. J Pharm Sci. 1998;87(11):1347–50.

    Article  CAS  PubMed  Google Scholar 

  • Labhasetwar V, Bonadio J, Goldstein S, Levy RJ. Gene transfection using biodegradable nanospheres: results in tissue culture and a rat osteotomy model. Colloids and Surfaces B: Biointerfaces. 1999;16:281–90.

    Article  CAS  Google Scholar 

  • Liu Y, Thor A, Shtivelman E, Cao Y, Tu G, Heath TD, et al. Systemic gene delivery expands the repertoire of effective antiangiogenic agents. J Biol Chem. 1999;274(19):13338–44.

    Article  CAS  PubMed  Google Scholar 

  • Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993;74(6):957–67.

    Article  CAS  PubMed  Google Scholar 

  • Olivier M, Petitjean A, Marcel V, Petre A, Mounawar M, Plymoth A, et al. Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Ther. 2009;16(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  • Panyam J, Labhasetwar V. Dynamics of endocytosis and exocytosis of poly(d, L-lactide-co-glycolide) nanoparticles in vascular smooth muscle cells. Pharm Res. 2003;20(2):212–20.

    Article  CAS  PubMed  Google Scholar 

  • Panyam J, Zhou WZ, Prabha S, Sahoo SK, Labhasetwar V. Rapid endo-lysosomal escape of poly(d, L-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. FASEB J. 2002;16(10):1217–26.

    Article  CAS  PubMed  Google Scholar 

  • Pisters LL, Pettaway CA, Troncoso P, McDonnell TJ, Stephens LC, Wood CG, et al. Evidence that transfer of functional p53 protein results in increased apoptosis in prostate cancer. Clin Cancer Res. 2004;10(8):2587–93.

    Article  CAS  PubMed  Google Scholar 

  • Prabha S, Labhasetwar V. Nanoparticle-mediated wild-type p53 gene delivery results in sustained antiproliferative activity in breast cancer cells. Mol Pharmaceutics. 2004a;1(3):211–9.

    Article  CAS  Google Scholar 

  • Prabha S, Labhasetwar V. Critical determinants in PLGA/PLA nanoparticle-mediated gene expression. Pharm Res. 2004b;21(2):354–64.

    Article  CAS  PubMed  Google Scholar 

  • Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008;9(5):402–12.

    Article  CAS  PubMed  Google Scholar 

  • Seki M, Iwakawa J, Cheng H, Cheng PW. p53 and PTEN/MMAC1/TEP1 gene therapy of human prostate PC-3 carcinoma xenograft, using transferrin-facilitated lipofection gene delivery strategy. Hum Gene Ther. 2002;13(6):761–73.

    Article  CAS  PubMed  Google Scholar 

  • Vasir J, Labhasetwar V. Biodegradable Nanoparticles In Gene Transfer: Delivery and Expression of DNA and RNA, A Laboratory Manual. Friedmann T and Rossi J, editors. Woodbury, NY: Cold Spring Harbor Laboratory Press; 2006.

  • Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408(6810):307–10.

    Article  CAS  PubMed  Google Scholar 

  • Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer. 2002;2(8):594–604.

    Article  CAS  PubMed  Google Scholar 

  • Wang NP, To H, Lee WH, Lee EY. Tumor suppressor activity of RB and p53 genes in human breast carcinoma cells. Oncogene. 1993;8(2):279–88.

    CAS  PubMed  Google Scholar 

  • Weill D, Mack M, Roth J, Swisher S, Proksch S, Merritt J, et al. Adenoviral-mediated p53 gene transfer to non-small cell lung cancer through endobronchial injection. Chest. 2000;118(4):966–70.

    Article  CAS  PubMed  Google Scholar 

  • Xu M, Kumar D, Srinivas S, Detolla LJ, Yu SF, Stass SA, et al. Parenteral gene therapy with p53 inhibits human breast tumors in vivo through a bystander mechanism without evidence of toxicity. Hum Gene Ther. 1997;8(2):177–85.

    Article  CAS  PubMed  Google Scholar 

  • Xu L, Pirollo KF, Chang EH. Tumor-targeted p53-gene therapy enhances the efficacy of conventional chemo/radiotherapy. J Control Release. 2001;74(1–3):115–28.

    Article  CAS  PubMed  Google Scholar 

  • Yu B, Tai HC, Xue W, Lee LJ, Lee RJ. Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol Membr Biol. 2010;27(7):286–98.

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Li Y, Li L, Zhang Y, Gao N, Zhang Z, et al. Phase I study of repeated intraepithelial delivery of adenoviral p53 in patients with dysplastic oral leukoplakia. J Oral Maxillofac Surg. 2009;67(5):1074–82.

    Article  PubMed  Google Scholar 

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Acknowledgments

The study reported here is funded by grant 1R01 EB 003975 from the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (to VL). Part of the animal studies was carried out at Nebraska Medical Center under the Nebraska Research Initiative Funds (to VL). IA is a predoctoral student in Cleveland Clinic’s Molecular Medicine Ph.D. Program, which is funded by the “Med into Grad” initiative of the Howard Hughes Medical Institute. IA is also supported by grant 1F31CA150566-01 from the National Cancer Institute of the National Institutes of Health.

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Authors declare no conflict.

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Author notes

  1. Wenxue Ma

    Present address: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

  2. Jayanth Panyam

    Present address: College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

Authors and Affiliations

  1. Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Blanka Sharma, Wenxue Ma, Isaac Morris Adjei, Jayanth Panyam, Sanja Dimitrijevic & Vinod Labhasetwar

  2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Vinod Labhasetwar

Authors
  1. Blanka Sharma
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  2. Wenxue Ma
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  3. Isaac Morris Adjei
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  4. Jayanth Panyam
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  5. Sanja Dimitrijevic
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  6. Vinod Labhasetwar
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Corresponding author

Correspondence to Vinod Labhasetwar.

Additional information

Blanka Sharma, Ph.D. and Wenxue Ma, M.D., Ph.D. contributed equally to this paper.

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Sharma, B., Ma, W., Adjei, I.M. et al. Nanoparticle-mediated p53 gene therapy for tumor inhibition. Drug Deliv. and Transl. Res. 1, 43–52 (2011). https://doi.org/10.1007/s13346-010-0008-9

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  • DOI: https://doi.org/10.1007/s13346-010-0008-9

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