Jeremy D Heidel

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (23)210.7 Total impact

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    ABSTRACT: Nanoparticle-based experimental therapeutics are currently being investigated in numerous human clinical trials. CALAA-01 is a targeted, polymer-based nanoparticle containing small interfering RNA (siRNA) and, to our knowledge, was the first RNA interference (RNAi)-based, experimental therapeutic to be administered to cancer patients. Here, we report the results from the initial phase I clinical trial where 24 patients with different cancers were treated with CALAA-01 and compare those results to data obtained from multispecies animal studies to provide a detailed example of translating this class of nanoparticles from animals to humans. The pharmacokinetics of CALAA-01 in mice, rats, monkeys, and humans show fast elimination and reveal that the maximum concentration obtained in the blood after i.v. administration correlates with body weight across all species. The safety profile of CALAA-01 in animals is similarly obtained in humans except that animal kidney toxicities are not observed in humans; this could be due to the use of a predosing hydration protocol used in the clinic. Taken in total, the animal models do appear to predict the behavior of CALAA-01 in humans.
    Proceedings of the National Academy of Sciences 07/2014; DOI:10.1073/pnas.1411393111 · 9.81 Impact Factor
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    Jeremy D Heidel, Thomas Schluep
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    ABSTRACT: Nanoparticles are being widely explored as potential therapeutics for numerous applications in medicine and have been shown to significantly improve the circulation, biodistribution, efficacy, and safety profiles of multiple classes of drugs. One leading class of nanoparticles involves the use of linear, cyclodextrin-containing polymers (CDPs). As is discussed in this paper, CDPs can incorporate therapeutic payloads into nanoparticles via covalent attachment of prodrug/drug molecules to the polymer (the basis of the Cyclosert platform) or by noncovalent inclusion of cationic CDPs to anionic, nucleic acid payloads (the basis of the RONDEL platform). For each of these two approaches, we review the relevant molecular architecture and its rationale, discuss the physicochemical and biological properties of these nanoparticles, and detail the progress of leading drug candidates for each that have achieved clinical evaluation. Finally, we look ahead to potential future directions of investigation and product candidates based upon this technology.
    02/2012; 2012:262731. DOI:10.1155/2012/262731
  • Jeremy D Heidel
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    ABSTRACT: Numerous nonviral systems have been developed for the delivery of nucleic acids to cultured cells and to particular cell types in vivo. These systems vary with regard to their toxicity, immunogenicity, and ability to target particular cell surface receptors and/or cell types. A class of linear cationic polymers containing the sugar β-cyclodextrin has been shown to be effective at delivering a variety of nucleic acids in vivo, including plasmid DNA, DNAzymes, and short interfering RNAs (siRNAs). These polymer-nucleic acid complexes (polyplexes) can be further modified to incorporate a targeting ligand such as transferrin to induce preferential uptake of polyplexes by cells expressing high levels of the cognate receptor. This article presents background information on cyclodextrin-containing polycations.
    Cold Spring Harbor Protocols 11/2011; 2011(11):1319-22. DOI:10.1101/pdb.top066639 · 4.63 Impact Factor
  • Jeremy D Heidel, Mark E Davis
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    ABSTRACT: Nanoparticle approaches to drug delivery for cancer offer exciting and potentially "game-changing" ways to improve patient care and quality of life in numerous ways, such as reducing off-target toxicities by more selectively directing drug molecules to intracellular targets of cancer cells. Here, we focus on technologies being investigated clinically and discuss numerous types of therapeutic molecules that have been incorporated within nanostructured entities such as nanoparticles. The impacts of nanostructured therapeutics on efficacy and safety, including parameters like pharmacokinetics and biodistribution, are described for several drug molecules. Additionally, we discuss recent advances in the understanding of ligand-based targeting of nanoparticles, such as on receptor avidity and selectivity.
    Pharmaceutical Research 02/2011; 28(2):187-99. DOI:10.1007/s11095-010-0178-7 · 3.95 Impact Factor
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    ABSTRACT: Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.
    Nature 03/2010; 464(7291):1067-70. DOI:10.1038/nature08956 · 42.35 Impact Factor
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    ABSTRACT: With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo. The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may be a particularly safe class of therapeutics.
    Nature medicine 10/2009; 15(10):1224-8. DOI:10.1038/nm.1990 · 28.05 Impact Factor
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    ABSTRACT: Immune suppression is a major cause of morbidity and mortality in the patients with sepsis. Apoptotic loss of immune effector cells such as CD4 T and B cells is a key component in the loss of immune competence in sepsis. Inhibition of lymphocyte apoptosis has led to improved survival in animal models of sepsis. Using quantitative real-time polymerase chain reaction of isolated splenic CD4 T and B cells, we determined that Bim and PUMA, two key cell death proteins, are markedly upregulated during sepsis. Lymphocytes have been notoriously difficult to transfect with small interfering RNA (siRNA). Consequently a novel, cyclodextrin polymer-based, transferrin receptor-targeted, delivery vehicle was used to coadminister siRNA to Bim and PUMA to mice immediately after cecal ligation and puncture. Antiapoptotic siRNA-based therapy markedly decreased lymphocyte apoptosis and prevented the loss of splenic CD4 T and B cells. Flow cytometry confirmed in vivo delivery of siRNA to CD4 T and B cells and also demonstrated decreases in intracellular Bim and PUMA protein. In conclusion, Bim and PUMA are two critical mediators of immune cell death in sepsis. Use of a novel cyclodextrin polymer-based, transferrin receptor-targeted siRNA delivery vehicle enables effective administration of antiapoptotic siRNAs to lymphocytes and reverses the immune cell depletion that is a hallmark of this highly lethal disorder.
    Shock (Augusta, Ga.) 12/2008; 32(2):131-9. DOI:10.1097/SHK.0b013e318194bcee · 2.73 Impact Factor
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    ABSTRACT: Calando Pharmaceuticals is developing a proprietary, targeted siRNA delivery platform, RONDEL (RNAi/oligonucleotide delivery), which formulates therapeutic siRNA into targeted nanoparticles. CALAA-01, Calando's lead nanoparticle drug candidate, contains an siRNA targeting the M2 subunit of ribonucleotide reductase (RRM2) for applications in cancer. Extensive characterizations have been performed on the physicochemical properties, in vitro efficacy, and in vivo safety of these nanoparticle formulations. CALAA-01 is currently in a Phase I human clinical trial, representing the first targeted systemic siRNA delivery in the clinics and the only clinical stage RNAi therapeutic oncology program. As a demonstration of the versatility of the RONDEL platform, Calando is also developing a second candidate, CALAA-02, which contains an siRNA targeting the hypoxia inducible factor-2 alpha (HIF-2α), for applications in cancer as well. CALAA-02 is currently in pre-clinical development.
    2008 AIChE Annual Meeting; 11/2008
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    ABSTRACT: The results of administering escalating, i.v. doses of targeted nanoparticles containing a siRNA targeting the M2 subunit of ribonucleotide reductase to non-human primates are reported. The nanoparticles consist of a synthetic delivery system that uses a linear, cyclodextrin-containing polycation, transferrin (Tf) protein targeting ligand, and siRNA. When administered to cynomolgus monkeys at doses of 3 and 9 mg siRNA/kg, the nanoparticles are well tolerated. At 27 mg siRNA/kg, elevated levels of blood urea nitrogen and creatinine are observed that are indicative of kidney toxicity. Mild elevations in alanine amino transferase and aspartate transaminase at this dose level indicate that the liver is also affected to some extent. Analysis of complement factors does not reveal any changes that are clearly attributable to dosing with the nanoparticle formulation. Detection of increased IL-6 levels in all animals at 27 mg siRNA/kg and increased IFN-gamma in one animal indicate that this high dose level produces a mild immune response. Overall, no clinical signs of toxicity clearly attributable to treatment are observed. The multiple administrations spanning a period of 17-18 days enable assessment of antibody formation against the human Tf component of the formulation. Low titers of anti-Tf antibodies are detected, but this response is not associated with any manifestations of a hypersensitivity reaction upon readministration of the targeted nanoparticle. Taken together, the data presented show that multiple, systemic doses of targeted nanoparticles containing nonchemically modified siRNA can safely be administered to non-human primates.
    Proceedings of the National Academy of Sciences 05/2007; 104(14):5715-21. DOI:10.1073/pnas.0701458104 · 9.81 Impact Factor
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    ABSTRACT: Ribonucleotide reductase (RR) is a therapeutic target for DNA replication-dependent diseases such as cancer. Here, a potent small interfering RNA (siRNA) duplex against the M2 subunit of RR (RRM2) is developed and shown to reduce the growth potential of cancer cells both in vitro and in vivo. Three anti-RRM2 siRNAs were identified via computational methods, and the potency of these and additional "tiling" duplexes was analyzed in cultured cells via cotransfections using a RRM2-luciferase fusion construct. Knockdown of RRM2 by the best duplex candidates was confirmed directly by Western blotting. The effect of potent duplexes on cell growth was investigated by a real-time cell electronic sensing assay. Finally, duplex performance was tested in vivo in luciferase-expressing cells via whole animal bioluminescence imaging. Moderate anti-RRM2 effects are observed from the three duplexes identified by computational methods. However, the tiling experiments yielded an extremely potent duplex (siR2B+5). This duplex achieves significant knockdown of RRM2 protein in cultured cells and has pronounced antiproliferative activity. S.c. tumors of cells that had been transfected with siR2B+5 preinjection grew slower than those of control cells. An anti-RRM2 siRNA duplex is identified that exhibits significant antiproliferative activity in cancer cells of varying human type and species (mouse, rat, monkey); these findings suggest that this duplex is a promising candidate for therapeutic development.
    Clinical Cancer Research 04/2007; 13(7):2207-15. DOI:10.1158/1078-0432.CCR-06-2218 · 8.19 Impact Factor
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    ABSTRACT: The linear, cyclodextrin-containing polycation (CDP) is one of many non-viral gene delivery vectors that show improved transfection efficiency when modified to have pH-buffering capacity. The buffering activity is presumed to confer enhanced ability to escape the endocytic pathway. Here, the differences in delivery behavior between CDP and its pH-buffering, imidazole-containing variant (CDPim) are investigated in order to elucidate the mechanism(s) by which these related materials exhibit differences in gene delivery. In cell-free assays that include dye exclusion and heparan sulfate displacement, CDP appears to have weaker binding strength with nucleic acids than CDPim. Numerous analyses involving transfected cells, however, indicate that CDPim more readily releases nucleic acids in the intracellular setting. Together, these data suggest that differences in transfection efficiency between CDP and CDPim result from factors beyond buffering activity and endosomal escape.
    Journal of Controlled Release 12/2006; 116(2):179-91. DOI:10.1016/j.jconrel.2006.06.018 · 7.26 Impact Factor
  • Jeremy D Heidel
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    ABSTRACT: Cyclodextrins, cyclic oligomers of glucose, have been used in pharmaceutical formulations for decades as a result to their biocompatibilities, low toxicities and their abilities to solubilise organic small molecules via inclusion complex formation. The incorporation of cyclodextrins within polymers of numerous types, for use as drug delivery agents, has been explored. Illustrative of the flexibility in polymer chemistry and delivery application that is possible with these materials, two linear cyclodextrin-containing polymers are in preclinical and clinical development for the non-covalent delivery of nucleic acid therapeutics and covalent delivery of a small-molecule drug, respectively. This document provides an overview of the background and progress that has been made with these materials thus far, as well as suggestions for their future development and characterisation.
    Expert Opinion on Drug Delivery 10/2006; 3(5):641-6. DOI:10.1517/17425247.3.5.641 · 4.12 Impact Factor
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    ABSTRACT: Preclinical efficacy of i.v. IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a cyclodextrin-based polymer, was investigated in several mouse xenografts. The effects of different multiple dosing schedules on tumor growth of LS174T colon carcinoma xenografts are elucidated. All multiple dosing schedules administered over 15 to 19 days resulted in enhanced efficacy compared with untreated or single-dose groups. Further improvements in antitumor efficacy were not observed when the dosing frequency was increased from three weekly doses to five doses at 4-day intervals or 5 days of daily dosing followed by 2 days without dosing repeated in three cycles using similar cumulative doses. This observation was attributed to the extended release characteristics of camptothecin from the polymer. Antitumor efficacy was further evaluated in mice bearing six different s.c. xenografts (LS174T and HT29 colorectal cancer, H1299 non-small-cell lung cancer, H69 small-cell lung cancer, Panc-1 pancreatic cancer, and MDA-MB-231 breast cancer) and one disseminated xenograft (TC71-luc Ewing's sarcoma). In all cases, a single treatment cycle of three weekly doses of IT-101 resulted in a significant antitumor effect. Complete tumor regression was observed in all animals bearing H1299 tumors and in the majority of animals with disseminated Ewing's sarcoma tumors. Importantly, IT-101 is effective in a number of tumors that are resistant to treatment with irinotecan (MDA-MB-231, Panc-1, and HT29), consistent with the hypothesis that polymeric drug conjugates may be able to overcome certain kinds of multidrug resistance. Taken together, these results indicate that IT-101 has good tolerability and antitumor activity against a wide range of tumors.
    Clinical Cancer Research 04/2006; 12(5):1606-14. DOI:10.1158/1078-0432.CCR-05-1566 · 8.19 Impact Factor
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    ABSTRACT: The development of effective, systemic therapies for metastatic cancer is highly desired. We show here that the systemic delivery of sequence-specific small interfering RNA (siRNA) against the EWS-FLI1 gene product by a targeted, nonviral delivery system dramatically inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. The nonviral delivery system uses a cyclodextrin-containing polycation to bind and protect siRNA and transferrin as a targeting ligand for delivery to transferrin receptor-expressing tumor cells. Removal of the targeting ligand or the use of a control siRNA sequence eliminates the antitumor effects. Additionally, no abnormalities in interleukin-12 and IFN-alpha, liver and kidney function tests, complete blood counts, or pathology of major organs are observed from long-term, low-pressure, low-volume tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted, nonviral siRNA delivery system.
    Cancer Research 11/2005; 65(19):8984-92. DOI:10.1158/0008-5472.CAN-05-0565 · 9.28 Impact Factor
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    ABSTRACT: Molecular Therapy (2005) 11, S28|[ndash]|S29; doi: 10.1016/j.ymthe.2005.06.048 70. Systemic Administration of siRNA Against EWS-FLI1 Using a Targeted, Non-Viral Formulation Inhibits Growth in a Disseminated Murine Model of Ewing's Sarcoma Jeremy D. Heidel1, Siwen Hu-Lieskovan2, Derek W. Bartlett1, Timothy J. Triche2 and Mark E. Davis1,|[ast]|1Chemical Engineering, California Institute of Technology, Pasadena, CA2Pathology, Children's Hospital-Los Angeles, Los Angeles, CA|[ast]|M.E.D. is a consultant to and has a financial interest in Insert Therapeutics, Inc.
    Molecular Therapy 04/2005; DOI:10.1016/j.ymthe.2005.06.048 · 6.43 Impact Factor
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    Derek W. Bartlett, Jeremy D. Heidel, Mark E. Davis
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    ABSTRACT: Molecular Therapy (2005) 11, S82|[ndash]|S82; doi: 10.1016/j.ymthe.2005.06.211 208. Physicochemical and Biological Characterization of Cyclodextrin-Based Polycation (CDP)/siRNA Composites Designed for Systemic Delivery Derek W. Bartlett1, Jeremy D. Heidel1 and Mark E. Davis1,|[ast]|1Chemical Engineering, California Institute of Technology, Pasadena, CA|[ast]|M.E.D. is a consultant to and has a financial interest in Insert Therapeutics, Inc.
    Molecular Therapy 04/2005; DOI:10.1016/j.ymthe.2005.06.211 · 6.43 Impact Factor
  • Jeremy Heidel, Swaroop Mishra, Mark E Davis
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    ABSTRACT: Molecular conjugates are nanometer-sized entities consisting of synthetic materials (lipids, polycations, targeting agents, and so on) and nucleic acids. These composites are delivery vehicles that function to provide the transport of nucleic acids to sites of action. Recently, great progress has been made in the construction of these nonviral delivery vehicles and the understanding of how they function in cells and animals. Here, we review some of the important issues in assembling molecular conjugates and understanding their behavior in biological fluids, cells, and animals. One of the largest challenges in the field of molecular conjugates is how to integrate the components into a workable system that exploits the combined attributes of the components without suffering losses due to the assembly of the system. We discuss some of the difficulties involved in the assembly of a functioning delivery system for in vivo use.
    Advances in Biochemical Engineering/Biotechnology 02/2005; 99:7-39. DOI:10.1007/10_002 · 2.60 Impact Factor
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    ABSTRACT: Synthetic RNA duplexes that are substrates for Dicer are potent triggers of RNA interference (RNAi). Blunt 27mer duplexes can be up to 100-fold more potent than traditional 21mer duplexes. Not all 27mer duplexes show increased potency. Evaluation of the products of in vitro dicing reactions using electrospray ionization mass spectrometry reveals that a variety of products can be produced by Dicer cleavage. Use of asymmetric duplexes having a single 2-base 3'-overhang restricts the heterogeneity that results from dicing. Inclusion of DNA residues at the ends of blunt duplexes also limits heterogeneity. Combination of asymmetric 2-base 3'-overhang with 3'-DNA residues on the blunt end result in a duplex form which directs dicing to predictably yield a single primary cleavage product. It is therefore possible to design a 27mer duplex which is processed by Dicer to yield a specific, desired 21mer species. Using this strategy, two different 27mers can be designed that result in the same 21mer after dicing, one where the 3'-overhang resides on the antisense (AS) strand and dicing proceeds to the 'right' ('R') and one where the 3'-overhang resides on the sense (S) strand and dicing proceeds to the 'left' ('L'). Interestingly, the 'R' version of the asymmetric 27mer is generally more potent in reducing target gene levels than the 'L' version 27mer. Strand targeting experiments show asymmetric strand utilization between the two different 27mer forms, with the 'R' form favoring S strand and the 'L' form favoring AS strand silencing. Thus, Dicer processing confers functional polarity within the RNAi pathway.
    Nucleic Acids Research 02/2005; 33(13):4140-56. DOI:10.1093/nar/gki732 · 9.11 Impact Factor
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    ABSTRACT: RNA interference (RNAi) is rapidly becoming the method of choice for the elucidation of gene function and the identification of drug targets. As with other oligonucleotide-based strategies, RNAi is envisioned to ultimately be useful as a human therapeutic. Unlike previous nucleic acid therapeutics, small interfering RNAs have the potential to elicit immune responses via interactions with Toll-like receptor 3 and trigger interferon responses like long, double-stranded RNA and its analogs, such as poly(I:C). Recently, the safety of siRNAs has been questioned because they have been shown to trigger an interferon response in cultured cells. We show here that it is possible to administer naked, synthetic siRNAs to mice and downregulate an endogenous or exogenous target without inducing an interferon response.
    Nature Biotechnology 01/2005; 22(12):1579-82. DOI:10.1038/nbt1038 · 39.08 Impact Factor

Publication Stats

2k Citations
210.70 Total Impact Points

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Institutions

  • 2008
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2004–2007
    • California Institute of Technology
      • Division of Chemistry and Chemical Engineering
      Pasadena, CA, United States