Skip to main content

Main menu

  • Home
  • Current Issue
  • Archive
  • Info for
    • Authors
    • Editorial Policies
    • Subscribers
    • Advertisers
    • Editorial Board
  • Other Publications
    • In Vivo
    • Cancer Genomics & Proteomics
    • Cancer Diagnosis & Prognosis
  • More
    • IIAR
    • Conferences
    • 2008 Nobel Laureates
  • About Us
    • General Policy
    • Contact
  • Other Publications
    • Anticancer Research
    • In Vivo
    • Cancer Genomics & Proteomics

User menu

  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Anticancer Research
  • Other Publications
    • Anticancer Research
    • In Vivo
    • Cancer Genomics & Proteomics
  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Anticancer Research

Advanced Search

  • Home
  • Current Issue
  • Archive
  • Info for
    • Authors
    • Editorial Policies
    • Subscribers
    • Advertisers
    • Editorial Board
  • Other Publications
    • In Vivo
    • Cancer Genomics & Proteomics
    • Cancer Diagnosis & Prognosis
  • More
    • IIAR
    • Conferences
    • 2008 Nobel Laureates
  • About Us
    • General Policy
    • Contact
  • Visit us on Facebook
  • Follow us on Linkedin
Research ArticleExperimental Studies

The Utility of Tumor-specifically Internalizing Peptides for Targeted siRNA Delivery into Human Solid Tumors

FRANK UN, BINGSEN ZHOU and YUN YEN
Anticancer Research November 2012, 32 (11) 4685-4690;
FRANK UN
Department of Molecular Pharmacology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA, U.S.A.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
BINGSEN ZHOU
Department of Molecular Pharmacology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA, U.S.A.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
YUN YEN
Department of Molecular Pharmacology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA, U.S.A.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: yyen@coh.org
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Background: Ribonucleotide reductase composed of the hRRM1 and hRRM2 subunits catalyzes the conversion of ribonucleotides to their corresponding deoxy forms for DNA replication. Anti-hRRM2 siRNA degrades hRRM2's mRNA and suppresses tumorigenesis. A Phase I clinical trial demonstrated its therapy potential. HN-1 represents a tumor-specifically internalizing peptide for targeted-drug delivery into human head and neck squamous cell carcinoma. Materials and Methods: Internalization of peptide was monitored by fluorescence microscopy. The peptide-siRNA conjugate was chemically synthesized. The hRRM2 expression was monitored by western blot analysis. Results: HN-1TYR (HN-1 with two N-terminally added tyrosines) was internalized by human head and neck or breast cancer cells. Anti-hRRM2 siRNAR (resistant to RNase degradation) was conjugated to HN-1TYR without compromising their properties. The treatment with HN-1TYR-anti-hRRM2 siRNAR partly suppressed the endogenously expressed hRRM2 in human breast cancer cells. Conclusion: Our results establish the utility of tumor-specifically internalizing peptides for targeted siRNA delivery into human cancer cells.

  • Cancer
  • delivery
  • peptide
  • siRNA
  • tumor-specifically internalizing peptide
  • hRRM1
  • hRRM2

Abbreviation: RR, ribonucleotide reductase, TSIP; tumor-specifically internalizing peptide; PKC, protein kinase C; HU, hydroxyurea; HNSCC, head and neck squamous cell carcinoma; PBS, phosphate buffered saline; NHDF, normal human dermal fibroblasts; hRRM2, human ribonucleotide reductase subunit M2; BLAST, basic local alignment search tool; EPR, enhanced permeability retention; siRNA, small-interference RNA.

Ribonucleotide reductase (RR) represents the pharmacological target of the prototypic antimetabolite drug hydroxyurea (HU), which is used to treat human head and neck carcinoma (or sarcoma), chronic myelogenous leukemia and other cancers (1). In mammalian cells, RR represents the sole enzyme catalyzing the reduction of ribonucleotides to their corresponding deoxy forms to provide dNTPs for DNA replication (2). RR is composed of the subunits hRRM1 and hRRM2 (2, 3). HU partly cross-inhibits RR composed of the hRRM1 and p53R2 (a homologue of hRRM2) subunits, which is involved in DNA repair (4). HU inhibits RR by quenching free radicals necessary for the catalysis (2), through generating its own free radicals via oxidative transformation (5). The HU-generated free radicals also react with other molecular entities, resulting in various side-effects (6). HU's short half-life necessitates administering at a higher dose, exacerbating the side-effects.

To avoid HU-induced side-effects, siRNA was used to inhibit RR (7). In a Phase I clinical trial, the siRNA was delivered using nanoparticles that exploit the enhanced permeability retention (EPR) effect to reach the tumors (8). To escalate intravenous drug dose, the diameter of nanoparticles was adjusted to avoid renal clearance (9), though it may trap unused drugs in circulation. The complex was self-assembled from cyclodextrin-containing polymers, polyethylene glycol (for stability), the nucleic acid (siRNA) and human transferrin (to target tumors) (9) though normal cells, like erythrocytes, express the cognate receptor (10). In plasma, beta-cyclodextrins may associate with cholesterol to form crystals in proximal tubule cells and cause nephrotoxicity (11). Upon administration, the siRNA-loaded nanoparticle partly suppressed hRRM2 in melanoma cells of patients (8).

Nevertheless, the above vector carries several limitations. Firstly, the EPR effect occurs inconsistently due to tumor heterogeneity, which may compromise the delivery (12-14). Secondly, its intratumoral distribution was not homogenous (15), as the siRNA-loaded nanoparticle weighs considerably more (~700-10,000 times) than the typical antibodies (~100 kd) that poorly penetrate solid tumors (16). Thirdly, the siRNA-loaded nanoparticle readily disintegrates in the kidney, resulting in rapid depletion (17). Cost-wise, it may be difficult to afford for patients with low-income or in developing countries. These considerations prompted the exploration of alternate delivery vectors. To date, several peptides have been successfully used to deliver siRNAs to tumors in vivo (18). HN-1 (~1 kd) is a tumor-specifically internalizing peptide (TSIP) previously isolated for the targeted-drug delivery into human head and neck squamous cell carcinoma (HNSCC) (19). Using HN-1, various anticancer drugs such as Taxol (20), PKCε-inhibiting peptide (21) and diphtheria toxin (22) or tumor-imaging agents such as radioisotopes (23), have been targeted to human HNSCC in vivo. Here, we describe that the treatment with the HN-1TYR-anti-hRRM2 siRNAR conjugate, partly suppresses the endogenously expressed hRRM2 in human breast cancer cells.

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Development of HN-1TYR. Internalization of HN-1TYR by human HNSCC cells. Fluorescence microscopy (phase-contrast optics of the corresponding views are shown in upper panels). Indicated cells were incubated with FITC- HN-1TYR (panels 2 and 4) at 37°C for 48 h, (magnification: ×100).

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

HN-1TYR targets human breast cancer. Internalization of HN-1TYR by human breast cancer cells. Fluorescence microscopy (phase-contrast optics of the corresponding views are shown in upper panels). Indicated cells were incubated with FITC-HN-1TYR (panels 2, 4 and 6) at 37°C for 48 h (magnification: ×100).

Materials and Methods

Cell lines. All cell lines were acquired from the American Type Culture Collection (Manassas, VA, USA). NHDF, KB, MCF-7, MDA-MB-468 and ZR-75 human cells were maintained in DMEM medium with 10% fetal bovine serum supplemented with antibiotics at 37°C in 10% CO2.

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

Development of FITC-HN-1TYR-anti-hRRM2 siRNAR. A. Cellular uptake. Human breast cancer MCF-7 cells were incubated with FITC-HN-1TYR-anti-hRRM2 siRNAR (67 nM) at 37°C for 48 h. Fluorescence microscopy was performed as described in Materials and Methods. (Magnification: ×100). Inset: an amplified view of an indicated (arrow) cell [N=nucleus; C=cytoplasm]. B. Suppression of the hRRM2 expression. MCF-7 cells were incubated with FITC-HN-1TYR-anti-hRRM2 siRNAR at 37°C. No transfection agent was used. Western blot analysis was performed as described in Materials and Methods. The band corresponding to hRRM2 or a non-specific protein (NSP) is indicated. Dose: Lane 1, none; lane 2, 67 nM; lane 3, 67 nM. Incubation time: lane 1, 24 h; lane 2, 24 h; lane 3, 48 h.

Fluorescence microscopy. Cells were placed in 8-chamber slides and incubated in the appropriate medium, as described (19). After treating with the indicated peptide, cells were fixed, mounted, and viewed using an Olympus fluorescence microscope at the Microscope Core Facility of City of Hope National Medical Center (Duarte, CA, USA).

Figure 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4.

Map of the peptide-drug trajectory. A schematic representation shows the projected path of a peptide-drug conjugate into human breast solid tumors.

Western blot analysis. Western blot analysis was performed using anti-human hRRM2 subunit antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) as the primary antibody, followed by alkaline-conjugated anti-mouse IgG antibody as the secondary antibody. The resulting blot was visualized via the enhanced chemilumescence method (24).

Peptide or siRNA synthesis. Peptide, siRNA, or peptide-siRNA was synthesized and purified to >95% at the Peptide Synthesis Core Facility of City of Hope National Medical Center (Duarte, CA, USA). The predicted molecular mass and purity was confirmed by mass spectrometry. For FITC-HN1 (TSPLNIHNGQKL) or FITC-HN-1TYR (YYTSPLNIHNGQKL), a fluorescent label was added at the NH2-terminus and the COOH-terminus was capped with an amide group. FITC-HN-1TYR-anti-hRRM2 siRNAR was prepared as described in text (see below).

Results and Discussion

Development of the targeted-delivery vector HN-1TYR. HN-1, a synthetic 12-mer TSLP, was isolated by screening a random peptide-displaying M13 bacteriophage-based library (19). It meets several criteria for targeted drug delivery into solid tumors. Firstly, HN-1 can translocate drugs across the cell membrane into the cytosol. This was originally inferred from the HN-1 internalization study performed using a fluorescent molecule as the cargo (19). More recently, HN-1 was shown to translocate a human protein kinase C-ε (PKC-ε) inhibiting peptide or diphtheria toxin used as therapeutic into human cancer cells (21, 22). Secondly, the uptake of HN-1 occurs in a tumor-specific manner. HN-1 is internalized by human HNSCC cells (i.e. MDA177Tu, MDA138Tu, MDA59Tu, MDA167Tu, MDA686Tu, MDA1986Tu, UMSCC1, UMSCC36) yet poorly by their normal counterparts (i.e. HOK16B, NOE oral epithelial cells) (19, 21). Similarly, HN-1 was internalized by human breast cancer cells (ex. MDA-MB231, SKBR3) but less efficiently by their normal counterpart (ex. MCF10A non-tumorigenic mammary epithelial cells) (21). Thirdly, HN-1 is capable of penetrating solid tumor, which is critical as >90% of human cancers represent solid tumors. This was indicated by the presence of intravenously injected HN-1 at the interior of solid tumors formed from MDA177Tu or MDA167Tu cells in a mouse xenograft model (19). An independent report confirmed that the intravenously injected HN1 localizes at the interior of solid tumors formed from UMSCC1 cells in vivo (21).

HN-1TYR, which consists of the parental HN-1 backbone with two extra tyrosine residues, was synthesized. Tyrosines were placed N-terminally as the presence of additional residues at this terminus did not interfere with the HN-1 internalization potential (19). HN-1TYR efficiently solublized in phosphate-buffered saline (PBS) solution. The addition of two tyrosines did not generate novel proteolytic sites. Next, human head and neck cancer KB cells were incubated with FITC-HN-1TYR at 37°C, for 48 h, as previously described (19). FITC-HN-1TYR, which represents fluorescein-conjugated HN-1TYR, was synthesized chemically (see Materials and Methods). It led to fluorescing KB cells. Fluorescence was detected throughout the cell and was not limited to the cell surface (Figure 1; panel 2; also see Figure 2). The enlarged fluorescent micrograph of a single cell (Figure 3A, inset) shows that the internalized peptide primarily resides at the cytoplasm consistent with the properties of the parental peptide HN-1 (19). In the original report describing the HN-1 isolation (19), its internalization was extensively documented using various experimental methods so it is not repeated here. Untreated KB cells exhibited little autofluorescence (Figure 1; panel 1), suggesting that the observed fluorescence (Figure 1; panel 2) was specifically due to the internalized FITC-HN-1TYR. In contrast, normal human dermal fibroblasts (NHDF) that were similarly incubated with FITC-HN-1TYR exhibited little fluorescence (Figure 1, panel 4). Thus, HN-1TYR retains the HNSCC-internalization potential.

HN-1TYR is internalized by human breast cancer cells. To identify additional cancer targets of HN-1 with the paucity of information regarding the cognate receptor, we relied on the common developmental lineage. Previously, a similar approach (i.e. ‘developmental histogenesis’) was used to identify cancer types with similar chemosensitivity (25). During embryonic development, surface ectodermal epithelium gives rise to three distinct structures—i.e. cranial structures, epidermal structures, ectodermal placodes (26). Cranial structures include multiple cell types within the oral cavity such as the secretory, duct-lining cells of the salivary, palatine of oral glands and the epithelial lining cells of the gums, palate, lips and paranasal sinuses. Epidermal structures include the duct-lining and secretory cells of mammary glands (27). In humans, breast cancer occurs most frequently in the duct (i.e. ductal carcinoma) or lobules (i.e. lobular carcinoma). This fact, along with the recent finding by Bao et al. that HN-1 is internalized by human breast cancer cells (21), prompted us to investigate whether HN-1TYR could be used to deliver drugs to breast cancer cells.

To examine this point, human breast cancer cells with varying ‘triple status’ were investigated. Triple status refers to the expression level of Her2 receptor, estrogen receptor (ER), and progesterone receptor (PR). Here, we used human breast cancer cells that are distinct from those used in the report by Bao et al. (21). ZR-75-1 cells, which overexpress Her2, are positive for the ER (16 fmol/mg protein) or PR (102 fmol/mg) expression (28, 29). MCF-7 cells, which express little Her2, are positive for the ER (43 fmol/mg protein) or PR (115 fmol/mg protein) expression (30-32). MDA-MB-468 cells, which express little Her2, contain little ER (4 fmol/mg protein) or PR (9 fmol/mg protein (28, 33). Incubation of ZR-75-1 (Figure 2, panel 4), MCF-7 (Figure 2, panel 6) or MDA-MB-468 (Figure 2, panel 2) with FITC-HN-1TYR at 37°C for 48 h led to fluorescing cells in all three cases. In contrast, untreated ZR-75-1 (Figure 2, panel 3), MCF-7 (Figure 2, panel 5) or MDA-MB-468 (Figure 2, panel 1) cells did not fluoresce, indicative of the lack of autofluorescence. Hence, like HN-1, HN-1TYR targets human breast cancer cells and the targeting may be independent of their triple status.

Development of HN-1TYR-anti-hRRM2 siRNAR for anticancer therapy. To avoid side-effects resulting from the HU chemotherapy, an anti-hRRM2 siRNA that suppresses RR by degrading the mRNA encoding its hRRM2 subunit was previously developed (7). To identify target site, the hRRM2 mRNA sequence was probed for the preferred 27-nucleotide sites using an algorithm designed for predicting end-energy differential and mRNA secondary structure (34). The resulting candidate were distinguished on the basis of their GC content and homology with non-hRRM2 genes using basic local alignment search tool (BLAST) search, which yielded 3 siRNA candidates. Subsequently, numerous duplexes in their immediate vicinities were analyzed, resulting in the identification of a single siRNA with a potent hRRM2 inhibiting property (7). Upon transfection (using lipofectamine), the anti-hRRM2 siRNA suppressed (40-60%) the hRRM2 protein level for as long as 5 days. Transfection of human colorectal adenocarcinoma HT-29 cells with the anti-hRRM2 siRNA led to a near complete cessation of their growth (7). The siRNA does not appear to elicit interferon response in vivo (8, 35).

To translocate across the cell membrane for cellular uptake, the above siRNA was conjugated to HN-1TYR. To avoid degradation by RNases in vivo, anti-hRRM2 siRNA was synthesized with fluorine, incorporated at its 2’-OH position to yield anti-hRRM2 siRNAR. FITC-HN-1TYR was conjugated to 5’-end of anti-hRRM2 siRNAR (antisense strand only) using hexynyl phosphoramidite linker to generate FITC-HN-1TYR-anti-hRRM2 siRNAR. Equimolar concentration of the above sense and antisense strands were hybridized to generate duplex siRNA (molecular mass of the conjugate: ~19.7 kd). The internalization potential of the conjugate was examined. MCF-7 breast cancer cells were incubated with FITC-HN-1TYR-anti-hRRM2 siRNAR at 37°C for 48 h, as described above. It led to fluorescing cells (Figure 3A). The inset shown in Figure 3A, representing the amplified view of a single treated cell, shows clearly that the conjugate localizes at the cytoplasm upon entry. Untreated MCF-7 cells did not fluoresce (panel 5 in Figure 2). Thus, HN-1TYR is capable of translocating anti-hRRM2 siRNAR into MCF-7 cells in vivo. Next, its effect on the hRRM2 expression was examined. MCF-7 cells were incubated with FITC-HN-1TYR-anti-hRRM2 siRNAR for the indicated time period, lysed, and the resulting cell lysate was analyzed by western blot analysis using an anti-human hRRM2 antibody as the primary antibody. It led to a partial reduction (ca. ~50%) in the level of the endogenously expressed hRRM2 (Figure 3B, lanes 2 or 3). The suppression was specific for hRRM2 as the expression level of an irrelevant protein (designated as “NSP” in Figure 3B, lanes 2 or 3) was not affected. Thus, the FITC-HN-1TYR-anti-hRRM2 siRNAR conjugate retains the hRRM2-suppressing property.

A key determinant for the successful siRNA therapy is delivery (36). To avoid side-effects, delivery vectors with tumor-homing potential are increasingly sought. For targeted-drug delivery into human solid tumors, multiple requirements must be met (see above). Minute, non-bioactive, tumor-specifically internalizing peptides such as HN-1 may provide a solution. In this report, we described the development of a conjugate composed of the HN-1TYR peptide and anti-hRRM2 siRNAR. Our results confirm earlier findings by others that peptides can mediate the transfer of siRNAs into human cells (18). As the uptake seems to occur independently of the ‘triple status’, it may be applicable for a wide spectrum of human breast cancers. The results also suggest that RR remains a tenable target for therapy. Novel chemotherapeutics inhibiting RR are currently being developed. Potentially, siRNAs may represent the next-generation drugs to target RR. Its specificity may be exploited to lessen side-effects while preserving their therapeutic potential. Further works are envisioned. Firstly, despite the recent report (37), the precise identity of the HN-1 receptor remains to be defined. Secondly, a HN-1 derived vector with the endosome-escaping potential may be developed (22). Thirdly, the tumor-suppressing potential of the conjugate will be examined using an animal model. Hopefully, these advances may lead to a safer, yet effective, form of anticancer therapy.

Acknowledgements

We thank Xiyong Liu and Shuya Hu for technical assistance, and C. Bassford, D. Drake and M. Kong for administrative assistance.

  • Received September 12, 2012.
  • Accepted September 24, 2012.
  • Copyright© 2012 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved

References

  1. ↵
    1. Helmann R
    : Current CML therapy: progress and dilemma. Leukemia 17: 1010-1012, 2003.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Reichard P,
    2. Ehrenberg A
    : Ribonucleotide reductase: radical enzyme. Science 221: 514-519, 1983.
    OpenUrlFREE Full Text
  3. ↵
    1. Xue L,
    2. Zhou B,
    3. Liu X,
    4. Qiu W,
    5. Jin Z,
    6. Yen Y
    : Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits. Cancer Res. 63: 980-986, 2003.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Saho J,
    2. Zhou B,
    3. Zhu L,
    4. Qiu W,
    5. Yuan YC,
    6. Xi B,
    7. Yen Y
    : In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Cancer Res 64: 1-6, 2004.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Young CW,
    2. Hodas S
    : Hydroxyurea: inhibitory effect on DNA metabolism. Science 146: 1172-1174, 1964..
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Platt OS
    : Hydroxurea for the treatment of sick cell anemia. New Engl J Med 358: 1362-1369, 2008.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Heidel JD,
    2. Liu JY,
    3. Yen Y,
    4. Zhou B,
    5. Heale BS,
    6. Rossi JJ,
    7. Bartlett DW,
    8. Davis E
    : Potent siRNA inhbitors of ribonucleotide reductase subnit RRM2 reduce cell proliferation in vitro and in vivo. Clin Cancer Res 13: 2207-2215, 2007.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Davis ME,
    2. Zuckerman JE,
    3. Choi CH,
    4. Seligson D,
    5. Tocher A,
    6. Alabi CA,
    7. Yen Y,
    8. Heidel JD,
    9. Ribas A
    : Evidence of RNAi in humans from systematically administered siRNA via targeted nanoparticles. Nature 464: 1067-1070, 2010.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Davis ME
    : The first targeted delivery of siRNA in humans via a self-assembling cyclodextrin polymer-based nanoparticle: from concept to clinic. MOl Pharm 6: 659-668, 2009.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Ponka P,
    2. Lok CN
    : The transferrin receptor: role in health and disease. Int. J. Biochem. Cell Biol 31: 1111-1137, 1999.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Frijlink HW,
    2. Eissens AC,
    3. Hefting NR,
    4. Poelstra K,
    5. Lerk CF,
    6. Meijer DK
    : The effect of parenterally administered cycodextrins on cholesterol levels in the rat. Pharm Res 8: 9-16, 1991.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Bae YH,
    2. Park K
    : Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 153: 198-205, 2011.
    OpenUrlPubMed
    1. Jain RK,
    2. Stylianopoulos T
    : Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7: 653-654, 2010.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Lammers T,
    2. Kiessling F,
    3. Hennink WE,
    4. Storm G
    : Drug targeting to tumors: Principles, pitfalls and (pre)clinical progress. J. Control. Release 161: 175-187, 2012.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Rahman MA,
    2. Amin AR,
    3. Wang X,
    4. Zuckerman JE,
    5. Choi CH,
    6. Zhou B,
    7. Wang DNS,
    8. Koennig L,
    9. Chen Z,
    10. Chen ZG,
    11. Yen Y,
    12. Davis ME,
    13. Shin DM
    : Systemic delivery of siRNA nanoparticles targeting RRM2 suppresses head and neck tumor growth. J Control Release 159: 384-392, 2012.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Bartlett DW,
    2. Davis ME
    : Physicochemical and biological characterization of targeted, nucleic acid-containing nanoparticles. Bioconjug Chem 18: 456-468, 2007.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Zuckerman JE,
    2. Choi CH,
    3. Han H,
    4. Davis ME
    : Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane. Proc Natl Acad Sci USA 109: 3137-3142, 2012.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Sioud M,
    2. Mobergslien A
    : Efficient siRNA targeted delivery into cancer cells by gastrin-releasing peptide. Bioconjug Chem 23: 1040-1049, 2012.
    OpenUrlCrossRef
  18. ↵
    1. Hong FD,
    2. Clayman GL
    : Isolation of a peptide for targeted drug delivery into human head and neck solid tumors. Cancer Res 60: 6551-6556, 2000.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Henri JT,
    2. McChesney JD,
    3. Lamb R,
    4. Venkataraman SK
    : Molecular construct suitable for targeted conjugates. U.S. Patent Appl 20090246211. 2009.
  20. ↵
    1. Bao L,
    2. Gorin MA,
    3. Zhang M,
    4. Ventura AC,
    5. Pomerantz WC,
    6. Merajver SD,
    7. Teknos TN,
    8. Mapp AK,
    9. Pan Q
    : Preclinical development of a bifunctional cancer cell homing, PKCepsilon inhibitory peptide for the treatment of head and neck cancer. Cancer Res 69: 5829-5834, 2009.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Potala S,
    2. Verma RS
    : Targeting head and neck squamous cell carcinoma using a novel fusion toxin-diphtheria toxin/HN-1. Mol Biol Rep 38: 1389-1397, 2010.
    OpenUrlPubMed
  22. ↵
    1. Zheng X
    : Specificity and feasibility of HN-5 peptide for diagnosis and targeted therapy of head and neck squamous cell carciomas. University of Texas Health Science Center at San Antonio, 2007.
  23. ↵
    1. Un F,
    2. Qi C,
    3. Prosser M,
    4. Wang N,
    5. Zhou B,
    6. Bronner C,
    7. Yen Y
    : Modulating ICBP90 to suppress human ribonucleotide reductase M2 induction restores sensitivity to hydroxyurea cytotoxicity. Anticancer Res 26: 2761-2767, 2006.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Berman JJ
    : Tumor classification: molecular analysis meets Aristotle. BMC Cancer 4: 10, 2004.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Gray H,
    2. Williams PL,
    3. Bannister LH
    : Gray's Anatomy: the anatomical basis of medicine and surgery. Churchill Livingstone, New York, 1995.
  26. ↵
    1. Wiseman BS,
    2. Werb Z
    : Stromal effects on mammary gland development and breast cancer. Science 296: 1389-1397, 2002.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Poutanen M,
    2. Moncharmont B,
    3. Vihko R
    : 17 beta-hydroxylated dehydrogenase gene expression in human breast cancer cells: regulation of expression by a progestin. Cancer Res 52: 290-294, 1992.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Scott GK,
    2. Daniel JC,
    3. Xiong X,
    4. Maki RA,
    5. Kabat D,
    6. Benz CC
    : Binding of an ETS-related protein within the DNAse I hypersensitive site of the HER2/neu promoter in human breast cancer cells. J Biol Chem 269: 19848-19858, 1994.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Chakraborty AK,
    2. Liang K,
    3. DiGiovanna MP
    : Co-targeting insulin-like growth factor 1 receptor and HER2: dramatic effects of HER2 inhibitors on nonoverexpressing breast cancer. Cancer Res 68: 1538-1545, 2008.
    OpenUrlAbstract/FREE Full Text
    1. Kim HJ,
    2. Cui X,
    3. Hilsenbeck SG,
    4. Lee AV
    : Progesterone receptor loss correlates with human epidermal growth factor receptor 2 overexpression in estrogen receptor-positive breast cancer. Clin. Cancer Res 12: 1013s-1018s, 2006.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Levenson AS,
    2. Jordan VC
    :MCF-7: the first hormone responsive breast cancer cell line. Cancer Res 57: 3071-3078, 1997.
    OpenUrlFREE Full Text
  31. ↵
    1. Savellano MD,
    2. Pogue BW,
    3. Hoopes PJ,
    4. Vitetta ES,
    5. Paulsen KD
    : Multiepitope HER2 targeting enhances photoimmunotherapy of HER2-overexpressing cancer cells with pyropheophorbide-a immunoconjugates. Cancer Res 65: 6371-6379, 2005.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Heale BS,
    2. Soifers HS,
    3. Bowers C,
    4. Rossi JJ
    : siRNA target site secondary structure predictions using local stable substructures. Nucleic Acids Res 33: e30, 2005.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Heidel JD,
    2. Hu S,
    3. Liu XF,
    4. Triche TJ,
    5. Davis ME
    : Lack of interferon response in animals to naked siRNAs. Nature Biotech 22: 1579-1582, 2004.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Burnett JC,
    2. Rossi JJ
    : RNA based therapeutics: current progress and future prospects. Chem Bio 19: 60-71, 2012.
    OpenUrl
  35. ↵
    1. Dudas J,
    2. Idler C,
    3. Sprinzl G,
    4. Bernko-Schnuerch A,
    5. Riechelmann H
    : Identification of HN-1 target in head and neck squamous cell carcinoma cells. ISRN Oncol 2011: 140316, 2011.
    OpenUrlPubMed
PreviousNext
Back to top

In this issue

Anticancer Research: 32 (11)
Anticancer Research
Vol. 32, Issue 11
November 2012
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
  • Back Matter (PDF)
  • Ed Board (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on Anticancer Research.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
The Utility of Tumor-specifically Internalizing Peptides for Targeted siRNA Delivery into Human Solid Tumors
(Your Name) has sent you a message from Anticancer Research
(Your Name) thought you would like to see the Anticancer Research web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
2 + 11 =
Solve this simple math problem and enter the result. E.g. for 1+3, enter 4.
Citation Tools
The Utility of Tumor-specifically Internalizing Peptides for Targeted siRNA Delivery into Human Solid Tumors
FRANK UN, BINGSEN ZHOU, YUN YEN
Anticancer Research Nov 2012, 32 (11) 4685-4690;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Reprints and Permissions
Share
The Utility of Tumor-specifically Internalizing Peptides for Targeted siRNA Delivery into Human Solid Tumors
FRANK UN, BINGSEN ZHOU, YUN YEN
Anticancer Research Nov 2012, 32 (11) 4685-4690;
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results and Discussion
    • Acknowledgements
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • Inhibiting miR-33b-5p Enhances Chemoresistance in Lung Adenocarcinoma by Targeting YWHAH to Regulate Epithelial-mesenchymal Transition
  • Relationship Between Mediterranean Diet, Cardiovascular Risk Factors, and Meningiomas: A Retrospective Study
  • PARP Inhibitor Sensitizes BRCA-mutant Pancreatic Cancer to Oxaliplatin by Suppressing the CDK1/BRCA1 Axis
Show more Experimental Studies

Similar Articles

Keywords

  • cancer
  • delivery
  • peptide
  • siRNA
  • tumor-specifically internalizing peptide
  • hRRM1
  • hRRM2
Anticancer Research

© 2023 Anticancer Research

Powered by HighWire