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Featured researches published by Dan Peer.


Nature Nanotechnology | 2007

Nanocarriers as an emerging platform for cancer therapy

Dan Peer; Jeffrey M. Karp; Seungpyo Hong; Omid C. Farokhzad; Rimona Margalit; Robert Langer

Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers have been approved for clinical use. However, to date, there are only a few clinically approved nanocarriers that incorporate molecules to selectively bind and target cancer cells. This review examines some of the approved formulations and discusses the challenges in translating basic research to the clinic. We detail the arsenal of nanocarriers and molecules available for selective tumour targeting, and emphasize the challenges in cancer treatment.


Science | 2008

Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target.

Dan Peer; Eun Jeong Park; Yoshiyuki Morishita; Christopher V. Carman; Motomu Shimaoka

Cyclin D1 (CyD1) is a pivotal cell cycle–regulatory molecule and a well-studied therapeutic target for cancer. Although CyD1 is also strongly up-regulated at sites of inflammation, its exact roles in this context remain uncharacterized. To address this question, we developed a strategy for selectively silencing CyD1 in leukocytes in vivo. Targeted stabilized nanoparticles (tsNPs) were loaded with CyD1–small interfering RNA (siRNA). Antibodies to β7 integrin (β7 I) were then used to target specific leukocyte subsets involved in gut inflammation. Systemic application of β7 I-tsNPs silenced CyD1 in leukocytes and reversed experimentally induced colitis in mice by suppressing leukocyte proliferation and T helper cell 1 cytokine expression. This study reveals CyD1 to be a potential anti-inflammatory target, and suggests that the application of similar modes of targeting by siRNA may be feasible in other therapeutic settings.


Proceedings of the National Academy of Sciences of the United States of America | 2007

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1.

Dan Peer; Pengcheng Zhu; Christopher V. Carman; Judy Lieberman; Motomu Shimaoka

Silencing gene expression by RNAi is a powerful method for exploring gene function and validating drug targets and potentially for therapy. Lymphocytes and other primary blood cells are resistant to lipid-based transfection in vitro and are difficult to target in vivo. We show here that antibody-protamine fusion proteins targeting the human integrin lymphocyte function-associated antigen-1 (LFA-1) efficiently deliver siRNAs and specifically induce silencing in primary lymphocytes, monocytes, and dendritic cells. Moreover, a fusion protein constructed from an antibody that preferentially recognizes activation-dependent conformational changes in LFA-1 selectively targets activated leukocytes and can be used to suppress gene expression and cell proliferation only in activated lymphocytes. The siRNA-fusion protein complexes do not cause lymphocyte activation or induce IFN responses. K562 cells expressing latent WT or constitutively activated LFA-1 engrafted in the lungs of SCID mice are selectively targeted by intravenously injected fusion protein–siRNA complexes, demonstrating the potential in vivo applicability of LFA-1-directed siRNA delivery.


Journal of the American Chemical Society | 2012

Nanoparticle Hydrophobicity Dictates Immune Response

Daniel F. Moyano; Meir Goldsmith; David J. Solfiell; Dalit Landesman-Milo; Oscar R. Miranda; Dan Peer; Vincent M. Rotello

Understanding the interactions of nanomaterials with the immune system is essential for the engineering of new macromolecular systems for in vivo applications. Systematic study of immune activation is challenging due to the complex structure of most macromolecular probes. We present here the use of engineered gold nanoparticles to determine the sole effect of hydrophobicity on the immune response of splenocytes. The gene expression profile of a range of cytokines (immunological reporters) was analyzed against the calculated log P of the nanoparticle headgroups, with an essentially linear increase in immune activity with the increase in hydrophobicity observed in vitro. Consistent behavior was observed with in vivo mouse models, demonstrating the importance of hydrophobicity in immune system activation.


International Journal of Cancer | 2004

Loading mitomycin C inside long circulating hyaluronan targeted nano-liposomes increases its antitumor activity in three mice tumor models.

Dan Peer; Rimona Margalit

The frequent overexpression of the hyaluronan receptors CD44 and RHAMM in cancer cells opens the door for targeting by the naturally‐occurring high‐Mr hyaluronan. This is the first time effective in vivo tumor targeting is reported for mitomycin C (MMC) loaded inside nano‐sized hyaluronan‐liposomes (denoted tHA‐LIP). The severe adverse effects of free MMC made it a rational candidate for an effective targeted carrier. In vitro, loading MMC inside tHA‐LIP increased drug potency 100‐fold, in cells overexpressing, but not in cells underexpressing, hyaluronan receptors. Both types of liposomes were non‐toxic and reduced MMC‐related toxicity in healthy C57BL/6 mice. In 3 tumor models, BALB/c bearing C‐26 solid tumors; C57BL/6 bearing B16F10.9 or (separately) D122 lung metastasis, tHA‐LIP were long‐circulating, 7‐fold and 70‐fold longer than nt‐LIP and free MMC, respectively. tHA‐LIP‐mediated MMC accumulation in tumor‐bearing lungs was 20% of injected dose, compared to 0.6% and 4% with free drug and nt‐LIP, respectively. Tumor‐free lungs showed low accumulation, irrespective of drug formulation. Key indicators of therapeutic responses, tumor progression, metastatic burden and survival, were superior (p < 0.001) in animals receiving MMC‐loaded tHA‐LIP, no treatment, MMC‐loaded nt‐LIP and free drug. In conclusion, tHA‐LIP perform as tumor‐targeted carriers, with promising prospects for treatment of tumors overexpressing hyaluronan receptors.


Biomaterials | 2010

The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation

Ranit Kedmi; Noa Ben-Arie; Dan Peer

Delivery of nucleic acids with positively charged lipid nanoparticles ((+)NPs) is widely used as research reagents and potentially for therapeutics due to their ability to deliver nucleic acids into the cell cytoplasm. However, in most reports little attention has been made to their toxic effects. In the present study, we performed comprehensive analyses of the potential toxicity associated with (+)NPs. Mice treated with (+)NPs showed increased liver enzyme release and body weight loss compared to mice treated with neutral or negatively charged NPs ((-)NPs), suggesting hepatotoxicity. Intravenous administration of (+)NPs induced interferon type I response and elevated mRNA levels of interferon responsive genes 15-25-fold higher than neutral and (-)NPs in different subsets of leukocytes. Moreover, treatment with (+)NPs provoked a dramatic pro-inflammatory response by inducing Th1 cytokines expression (IL-2, IFN gamma and TNF alpha) 10-75-fold higher than treatment with control particles. Finally, we showed that activation of TLR4 might serve as the underlying mechanism for induction of an immune response when (+)NPs are used. These results suggest that a careful attention must be made when different types of (+)NPs are being developed as nanotherapeutics.


Molecular Therapy | 2010

RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice.

Sangsoo Kim; Dan Peer; Priti Kumar; Sandesh Subramanya; Huaquan Wu; Deshratan Asthana; Katsuyoshi Habiro; Yong-Guang Yang; N. Manjunath; Motomu Shimaoka; Premlata Shankar

RNA interference (RNAi)-mediated knockdown of gene expression offers a novel treatment strategy for human immunodeficiency virus (HIV) infection. However, the major hurdle for clinical use is a practical strategy for small interfering RNA (siRNA) delivery to the multiple immune cell types important in viral pathogenesis. We have developed a novel immunoliposome method targeting the lymphocyte function-associated antigen-1 (LFA-1) integrin expressed on all leukocytes and evaluated it for systemic delivery of siRNA in a humanized mouse model. We show that in vivo administration of the LFA-1 integrin-targeted and stabilized nanoparticles (LFA-1 I-tsNPs) results in selective uptake of siRNA by T cells and macrophages, the prime targets of HIV. Further, in vivo administration of anti-CCR5 siRNA/LFA-1 I-tsNPs resulted in leukocyte-specific gene silencing that was sustained for 10 days. Finally, humanized mice challenged with HIV after anti-CCR5 siRNA treatment showed enhanced resistance to infection as assessed by the reduction in plasma viral load and disease-associated CD4 T-cell loss. This study demonstrates the potential in vivo applicability of LFA-1-directed siRNA delivery as anti-HIV prophylaxis.


Chemical Society Reviews | 2012

Polysaccharides as building blocks for nanotherapeutics

Shoshy Mizrahy; Dan Peer

The use of polysaccharides as building blocks in the development of nano-sized drug delivery systems is rapidly growing. This can be attributed to the outstanding virtues of polysaccharides such as biocompatibility, biodegradability, low toxicity and low cost. In addition, the variety of physicochemical properties and the ease of chemical modifications enable the preparation of a wide array of nanoparticles. This tutorial review describes the properties of common polysaccharides, the main mechanisms for polysaccharide based-nanoparticles preparation, and provides examples from the conceptual design towards pre-clinical and clinical applications.


Journal of Controlled Release | 2011

Hyaluronan-coated nanoparticles: The influence of the molecular weight on CD44-hyaluronan interactions and on the immune response

Shoshy Mizrahy; Sabina Rebe Raz; Martin Hasgaard; Hong Liu; Neta Soffer-Tsur; Keren Cohen; Ram Dvash; Dalit Landsman-Milo; Maria G.E.G. Bremer; S. Moein Moghimi; Dan Peer

Hyaluronan (HA), a naturally occurring glycosaminoglycan, exerts different biological functions depending on its molecular weight ranging from 4000-10M Da. While high Mw HA (HMw-HA) is considered as anti-inflammatory, low Mw HA (LMw-HA) has been reported to activate an innate immune response. In addition, opposing effects on cell proliferation mediated by the HA receptor CD44, have also been reported for high and low Mw HA. We have previously demonstrated that HMw-HA can be covalently attached to the surface of lipid nanoparticles (NPs), endowing the carriers with long circulation and active targeting towards HA-receptors (CD44 and CD168) highly expressed on tumors. Here we present a small library of HA-coated NPs distinguished only by the Mw of their surface anchored HA ranging from 6.4 kDa to 1500 kDa. All types of NPs exerted no effect on macrophages, T cells and ovarian cancer cells proliferation. In addition, no induction of cytokines or complement activation was observed. The affinity towards the CD44 receptor was found to be solely controlled by the Mw of the NPs surface-bound HA, from extremely low binding for LMw-HA to binding with high affinity for HMw-HA. These findings have major implications for the use of HA in nanomedicine as LMw-HA surface modified-NPs could be a viable option for the replacement of polyethylene glycol (PEG) when passive delivery is required, lacking adverse effects such as complement activation and cytokine induction, while HMw-HA-coated NPs could be used for active targeting to CD44 overexpressing tumors and aberrantly activated leukocytes in inflammation.


ACS Nano | 2014

Nanoparticles for Imaging, Sensing, and Therapeutic Intervention

Lara K. Bogart; Geneviève Pourroy; Catherine J. Murphy; Victor Puntes; Teresa Pellegrino; Daniel Rosenblum; Dan Peer; Raphaël Lévy

Nanoparticles have the potential to contribute to new modalities in molecular imaging and sensing as well as in therapeutic interventions. In this Nano Focus article, we identify some of the current challenges and knowledge gaps that need to be confronted to accelerate the developments of various applications. Using specific examples, we journey from the characterization of these complex hybrid nanomaterials; continue with surface design and (bio)physicochemical properties, their fate in biological media and cells, and their potential for cancer treatment; and finally reflect on the role of animal models to predict their behavior in humans.

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