Dmitri Simberg

University of Colorado, Denver, Colorado, United States

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Publications (23)132.24 Total impact

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    ABSTRACT: One of the core issues of nanotechnology involves masking the foreignness of nanomaterials to enable in vivo longevity and long-term immune evasion. Dextran-coated superparamagnetic iron oxide nanoparticles are very effective magnetic resonance imaging (MRI) contrast agents, and strategies to prevent immune recognition are critical for their clinical translation. Here we prepared 20 kDa dextran-coated SPIO nanoworms (NWs) of 250 nm diameter and a high molar transverse relaxivity rate R2 (~400 mM-1 s-1) to study the effect of crosslinking-hydrogelation with 1-chloro-2, 3-epoxypropane (epichlorohydrin) on the immune evasion both in vitro and in vivo. Crosslinking was performed in the presence of different concentrations of NaOH (0.5 to 10 N) and different temperatures (23 and 37 °C). Increasing NaOH concentration and temperature significantly decrease the binding of anti-dextran antibody and dextran-binding lectin Conconavalin A to the NWs. The decrease in dextran immunoreactivity correlated with the decrease in opsonization by complement component 3 (C3) and with the decrease in the binding of the lectin complement pathway factor MASP-2 in mouse serum, suggesting that crosslinking blocks the lectin pathway of complement. The decrease in C3 opsonization correlated with the decrease in NW uptake by murine peritoneal macrophages. Optimized NWs demonstrated up to 10 hours circulation half-life in mice and minimal uptake by the liver, while maintaining the large 250 nm size in blood. In conclusion, we demonstrate that immune recognition of large iron oxide nanoparticles can be efficiently blocked by chemical crosslinking-hydrogelation, which is a promising strategy to improve safety and bioinertness of MRI contrast agents.
    ACS Nano 11/2014; · 12.03 Impact Factor
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    ABSTRACT: Background The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens. Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. However, dextran SPIO has been associated with significant number of complement-related side effects in patients and some agents have been discontinued from clinical use (e.g., Feridex¿). In order to improve the safety of these materials, the mechanisms of complement activation by dextran-coated SPIO and the differences between mice and humans need to be fully understood.Methods20 kDa dextran coated SPIO nanoworms (SPIO NW) were synthesized using Molday precipitation procedure. In vitro measurements of C3 deposition on SPIO NW using sera genetically deficient for various components of the classical pathway (CP), lectin pathway (LP) or alternative pathway (AP) components were used to study mechanisms of mouse complement activation. In vitro measurements of fluid phase markers of complement activation C4d and Bb and the terminal pathway marker SC5b-C9 in normal and genetically deficient sera were used to study the mechanisms of human complement activation. Mouse data were analyzed by non-paired t-test, human data were analyzed by ANOVA followed by multiple comparisons with Student-Newman-Keuls test.ResultsIn mouse sera, SPIO NW triggered the complement activation via the LP, whereas the AP contributes via the amplification loop. No involvement of the CP was observed. In human sera the LP together with the direct enhancement of the AP turnover was responsible for the complement activation. In two samples out of six healthy donors there was also a binding of anti-dextran antibodies and C1q, suggesting activation via the CP, but that did not affect the total level of C3 deposition on the particles.Conclusions There were important differences and similarities in the complement activation by SPIO NW in mouse versus human sera. Understanding the mechanisms of immune recognition of nanoparticles in mouse and human systems has important preclinical and clinical implications and could help design more efficient and safe nano-formulations.
    Particle and Fibre Toxicology 11/2014; · 9.18 Impact Factor
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    ABSTRACT: Lipid monolayer coated microbubbles are currently being developed to identify vascular regions that express certain surface proteins as part of the new technique of ultrasound molecular imaging. The microbubbles are functionalized with targeting ligands which bind to the desired cells holding the microbubbles in place as the remaining unbound microbubbles are eliminated from circulation. Subsequent scanning with ultrasound can detect the highly reflectant microbubbles that are left behind. The ultrasound scanning and detection process results in the destruction of the microbubble, creating lipid fragments from the monolayer. Here we demonstrate that microbubbles targeted to 4T1 murine breast cancer cells and human umbilical cord endothelial cells leave behind adhered fragments of the lipid monolayer after exposure to ultrasound with peak negative pressures of 0.18 and 0.8MPa. Most of the observed fragments were large enough to be resistant to receptor mediated endocytosis. The fragments were not observed to incorporate into the lipid membrane of the cell over a period of 96min. They were not observed to break into smaller pieces or significantly change shape but they were observed to undergo translation and rotation across the cell surface as the cells migrated over the substrate. These large fragments will apparently remain on the surface of the targeted cells for significant periods of time and need to be considered for their potential effects on blood flow through the microcapillaries and potential for immune system recognition.
    Ultrasonics 07/2014; · 2.03 Impact Factor
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    ABSTRACT: There is a great interest in targeting and selective ablation of populations of circulating cells for research or therapeutic purposes. Red blood cells (RBCs) are readily available and fully biocompatible long-circulating intravascular carriers (natural life is 120 days) that are amenable to chemical modifications, drug loading and reinjection. Here we demonstrate that using our previously described lipophilic ligand painting strategy, red blood cells (RBCs) could be in one step converted into targeted entities that selectively seek and bind various cells in vitro and in vivo. In vitro, RBCs modified with lipophilic anti-EpCAM or anti-CD45 antibodies efficiently bound to cancer cells and leukocytes, forming characteristic rosettes. In vivo, intravenously injected RBCs painted with anti-CD45 antibody immediately associated with CD45 positive cells in blood, forming RBC-leukocyte rosettes. Moreover, anti-CD45-modified RBCs, but not the same amount of anti-CD45 antibody or anti-CD45-lipid conjugate (1-2 μg/mouse), depleted over 50% of CD45+ leukocytes from circulation, with main clearance organs of leukocytes being liver and spleen with no visible deposition in kidneys and lungs. Anti-CD20 (Rituximab)-painted RBCs efficiently (over 90%) depleted CD19+/CD20+/CD45+ human lymphoma cells in mantle cell lymphoma (MCL) JeKo-1 model, while the same amount of rituximab-lipid (2 μg/mouse) was much less efficient in lymphoma cell depletion. Treatment of MCL mice with rituximab-modified RBCs carrying only 2 μg of the antibody resulted in a significant prolongation of survival as compared to the same amount of antibody-lipid control. Lipophilic ligand-painted RBCs is a novel tool that can be utilized for targeting blood borne cells for experimental immunology and drug delivery applications.
    Journal of Controlled Release 03/2014; · 7.63 Impact Factor
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    ABSTRACT: Although enzymes of non-human origin have been studied for a variety of therapeutic and diagnostic applications, their use has been limited by the immune responses generated against them. The described dual-porosity hollow nanoparticle platform obviates immune attack on non-human enzymes paving the way to in vivo applications including enzyme-prodrug therapies and enzymatic depletion of tumor nutrients. This platform is manufactured with a versatile, scalable, and robust fabrication method. It efficiently encapsulates macromolecular cargos filled through mesopores into a hollow interior, shielding them from antibodies and proteases once the mesopores are sealed with nanoporous material. The nanoporous shell allows small molecule diffusion allowing interaction with the large macromolecular payload in the hollow center. The approach has been validated in vivo using L-asparaginase to achieve L-asparagine depletion in the presence of neutralizing antibodies. Keywords: Nanomedicine; Nanoparticles; Enzyme Encapsulation; Non-human Enzymes; Silica; Immune Response.
    Nano Letters 01/2014; · 13.03 Impact Factor
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    ABSTRACT: With the emerging interest in personalized medicine, there is strong demand for new technologies for clinical sample interrogation. Exfoliated tumor cells in variety of pathological samples (e.g., blood, bone marrow, urine) could provide invaluable information for diagnosis and prognosis of cancers. Here we describe a detailed method for capture and isolation of tumor cells in medium, blood, or large-volume buffy coat using EpCAM-targeted buoyant microbubbles (MBs). Perflorohexane gas lipid shell MBs were prepared with emulsification method and conjugated with antibody as described by us before [25]. The binding of EpCAM-targeted MBs to A549 (human lung carcinoma) and 4T1 (mouse breast carcinoma) cells spiked into BSA/PBS or blood was more than 90%, which was comparable with commercial anti-EpCAM immunomagnetic beads (DynaBeads). Anti-EpCAM MBs efficiently (75-82%) isolated BxPC3 pancreatic tumor cells spiked into medium, blood or a buffy coat, within 15-30 min of incubation. We discuss MB parameters and experimental conditions critical to achieve efficient cells binding and isolation. In conclusion, MB-assisted cell isolation is a promising method for rapid enrichment of cells and biomarkers from biological samples.
    Methods 08/2013; · 3.64 Impact Factor
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    ABSTRACT: Red blood cells (RBCs) attract significant interest as carriers of biomolecules, drugs, and nanoparticles. In this regard, versatile technologies to attach molecules and ligands to the RBC surface are of great importance. Reported here is a fast and efficient surface painting strategy to attach ligands to the surface of RBCs, and the factors that control the stability and circulation properties of the modified RBCs in vivo. Distearoyl phosphatidylethanolamine anchor-conjugated immunoglobulin (IgG) efficiently incorporates in the RBC membrane following 15-30 min incubation. The optimized RBCs show prolonged circulation in vivo (70% of the injected dose after 48 h) and efficient retention of IgG in the membrane with terminal half-life of 73 h. The IgG construct is gradually lost from the RBCs mainly due to the transfer to plasma components, liver endothelial cells, and Kupffer cells. The ligand retention efficiency is partially dictated by ligand type, anchor type, and ligand concentration in the membrane, while RBC half-life is determined by initial concentration of the ligand in the membrane and presence of PEG linker between the ligand and the anchor. This work provides important guidance for non-covalent surface painting of RBCs as well as other types of blood borne cells for in vivo therapeutic and targeting applications.
    Advanced healthcare materials. 06/2013;
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    ABSTRACT: Scavenger receptors (SRs) are molecular pattern recognition receptors that have been shown to mediate opsonin-independent uptake of therapeutic and imaging nanoparticles, underlying the importance of SRs in nanomedicine. Unlike pathogens, engineered nanomaterials offer great flexibility in control of surface properties, allowing addressing specific questions regarding the molecular mechanisms of nanoparticle recognition. Recently we showed that SR type AI/II mediates opsonin-independent internalization of dextran-superparamagnetic iron oxide (SPIO) nanoparticles via positively charged extracellular collagen-like domain. In order to understand the mechanism of opsonin-independent SPIO recognition, we tested the binding and uptake of nanoparticles with different surface coatings by SR-AI. SPIO coated with 10kDa dextran was efficiently recognized and taken up by SR-AI transfected cells and J774 macrophages, while SPIO with 20kDa dextran coating or crosslinked dextran hydrogel avoided the binding and uptake. Nanoparticle negative charge density and zeta potential did not correlate with SR-AI binding/uptake efficiency. Additional experiments and computer modeling revealed that recognition of iron oxide crystalline core by positively charged collagen-like domain of SR-AI is sterically hindered by surface polymer coating. Importantly, the modeling revealed a strong complementarity between the surface Fe-OH groups of the magnetite crystal and the charged lysines of collagen-like domain of SR-AI, suggesting a specific recognition of SPIO crystalline surface. These data provide an insight into the molecular recognition of nanocrystals by innate immunity receptors and the mechanisms whereby polymer coatings promote immune evasion.
    ACS Nano 04/2013; · 12.03 Impact Factor
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    ABSTRACT: Staurosporine (STS) is a potent pan-kinase inhibitor with marked activity against several chemotherapy-resistant tumor types in vitro. The translational progress of this compound has been hindered by poor pharmacokinetics and toxicity. We sought to determine whether liposomal encapsulation of STS would enhance antitumor efficacy and reduce toxicity, thereby supporting the feasibility of further preclinical development. We developed a novel reverse pH gradient liposomal loading method for STS, with an optimal buffer type and drug-to-lipid ratio. Our approach produced 70% loading efficiency with good retention, and we provide, for the first time, an assessment of the in vivo antitumor activity of STS. A low intravenous dose (0.8 mg/kg) inhibited U87 tumors in a murine flank model. Biodistribution showed preferential tumor accumulation, and body weight data, a sensitive index of STS toxicity, was unaffected by liposomal STS, but did decline with the free compound. In vitro experiments revealed that liposomal STS blocked Akt phosphorylation, induced poly(ADP-ribose) polymerase cleavage, and produced cell death via apoptosis. This study provides a basis to explore further the feasibility of liposomally encapsulated STS, and potentially related compounds for the management of resistant solid tumors.
    International Journal of Nanomedicine 01/2013; 8:3991-4006. · 4.20 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTCs) are exfoliated at various stages of cancer, and could provide invaluable information for the diagnosis and prognosis of cancers. There is an urgent need for the development of cost-efficient and scalable technologies for rare CTC enrichment from blood. Here we report a novel method for isolation of rare tumor cells from excess of blood cells using gas-filled buoyant immuno-microbubbles (MBs). MBs were prepared by emulsification of perfluorocarbon gas in phospholipids and decorated with anti-epithelial cell adhesion molecule (EpCAM) antibody. EpCAM-targeted MBs efficiently (85%) and rapidly (within 15 minutes) bound to various epithelial tumor cells suspended in cell medium. EpCAM-targeted MBs efficiently (88%) isolated frequent tumor cells that were spiked at 100,000 cells/ml into plasma-depleted blood. Anti-EpCAM MBs efficiently (>77%) isolated rare mouse breast 4T1, human prostate PC-3 and pancreatic cancer BxPC-3 cells spiked into 1, 3 and 7 ml (respectively) of plasma-depleted blood. Using EpCAM targeted MBs CTCs from metastatic cancer patients were isolated, suggesting that this technique could be developed into a valuable clinical tool for isolation, enumeration and analysis of rare cells.
    PLoS ONE 01/2013; 8(3):e58017. · 3.53 Impact Factor
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    ABSTRACT: Dextran-coated superparamagnetic iron oxide nanoparticles (dextran-SPIO conjugates) offer the attractive possibility of enhancing MRI imaging sensitivity so that small or diffuse lesions can be detected. However, systemically injected SPIOs are rapidly removed by macrophages. We engineered embryonic cells (HEK293T) to express major macrophage scavenger receptor (SR) subtypes including SR-AI, MARCO, and endothelial receptor collectin-12. These SRs possess a positively charged collagen-like (CL) domain and they promoted SPIO uptake, while the charge neutral lipoprotein receptor SR-BI did not. In silico modeling indicated a positive net charge on the CL domain and a net negative charge on the cysteine-rich (CR) domain of MARCO and SR-AI. In vitro experiments revealed that CR domain deletion in SR-AI boosted uptake of SPIO 3-fold, while deletion of MARCO's CR domain abolished this uptake. These data suggest that future studies might productively focus on the validation and further exploration of SR charge fields in SPIO recognition.
    Bioconjugate Chemistry 04/2012; · 4.58 Impact Factor
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    ABSTRACT: Premature recognition and clearance of nanoparticulate imaging and therapeutic agents by macrophages in the tissues can dramatically reduce both the nanoparticle half-life and delivery to the diseased tissue. Grafting nanoparticles with hydrogels prevents nanoparticulate recognition by liver and spleen macrophages and greatly prolongs circulation times in vivo. Understanding the mechanisms by which hydrogels achieve this "stealth" effect has implications for the design of long-circulating nanoparticles. Thus, the role of plasma protein absorption in the hydrogel effect is not yet understood. Short-circulating dextran-coated iron oxide nanoparticles could be converted into stealth hydrogel nanoparticles by cross-linking with 1-chloro-2,3-epoxypropane. We show that hydrogelation did not affect the size, shape and zeta potential, but completely prevented the recognition and clearance by liver macrophages in vivo. Hydrogelation decreased the number of hydroxyl groups on the nanoparticle surface and reduced the binding of the anti-dextran antibody. At the same time, hydrogelation did not reduce the absorption of cationic proteins on the nanoparticle surface. Specifically, there was no effect on the binding of kininogen, histidine-rich glycoprotein, and protamine sulfate to the anionic nanoparticle surface. In addition, hydrogelation did not prevent activation of plasma kallikrein on the metal oxide surface. These data suggest that (a) a stealth hydrogel coating does not mask charge interactions with iron oxide surface and (b) the total blockade of plasma protein absorption is not required for maintaining iron oxide nanoparticles' long-circulating stealth properties. These data illustrate a novel, clinically promising property of long-circulating stealth nanoparticles.
    Molecular Pharmaceutics 03/2012; 9(3):539-45. · 4.57 Impact Factor
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    ABSTRACT: Chemotherapy is one of the frontline treatments for cancer patients, but the toxic side effects limit its effectiveness and potential. The goal of drug delivery is to reduce these side effects by encapsulating the drugs in a carrier which prevents release and can circulate throughout the body causing minimal damage to the healthy tissue. Slow release carriers have been developed which reduce the exposure to healthy tissue but this slow release also limits the maximum levels of drug in the tumor and nonspecific accumulation in healthy tissue remains a major hurdle. The next advance is to design these carriers to produce a rapid burst release of drug, but only in response to a localized trigger. The trigger of choice is low intensity focused ultrasound. A new particle is described here which incorporates an ultrasound sensitive microbubble of perfluorocarbon gas within a protective liposome carrier along with the payload. It is shown that this design can accomplish the desired burst release when exposed to ultrasound focused to small spatial locations within tissue phantoms. The ability to trigger release could provide a second level of spatial and temporal control beyond biochemical targeting or passive accumulation, making these promising particles for further development.
    Advances in experimental medicine and biology 01/2012; 733:145-53. · 1.83 Impact Factor
  • Ying Chao, Priya Prakash Karmali, Dmitri Simberg
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    ABSTRACT: Superparamagnetic iron oxide (SPIO, Ferumoxides, Feridex), an important MRI intravenous contrast reagent, is efficiently recognized and eliminated by macrophages in the liver, spleen, lymph nodes and atherosclerotic lesions. The receptors that recognize nanoparticles are poorly defined and understood. Since SPIO is coated with bacterial polysaccharide dextran, it is important to know whether carbohydrate recognition plays a role in nanoparticle uptake by macrophages. Lectin-like receptors CD206 (macrophage mannose receptor) and SIGNR1 were previously shown to mediate uptake of bacterial polysaccharides. We transiently expressed receptors MGL-1, SIGNR-1 and msDectin-1 in non-macrophage 293T cells using lipofection. The expression was confirmed by reverse transcription PCR. Following incubation with the nanoparticles, the uptake in receptor-expressing cells was not statistically different compared to control cells (GFP-transfected). At the same time, expression of scavenger receptor SR-A1 increased the uptake of nanoparticles three-fold compared to GFP-transfected and control vector-transfected cells. Blocking CD206 with anti-CD206 antibody or with the ligand mannan did not affect SPIO uptake by J774.A1 macrophages. Similarly, there was no inhibition of the uptake by anti-CD11b (Mac-1 integrin) antibody. Polyanionic scavenger receptor ligands heparin, polyinosinic acid, fucoidan and dextran sulfate decreased the uptake of SPIO by J774A.1 macrophages and Kupffer cells by 60-75%. These data unambiguously show that SPIO is taken up via interaction by scavenger receptors, but not via dextran recognition by carbohydrate receptors. Understanding of nanoparticle-receptor interaction can provide guidance for the design of long circulating, non-toxic nanomedicines.
    Advances in experimental medicine and biology 01/2012; 733:115-23. · 1.83 Impact Factor
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    ABSTRACT: Certain nanoparticles act as nucleation sites for acoustic cavitation. Their surface roughness and hydrophobic regions can decrease the pressure required to induce the cavitation event. This concept has been examined for potential to provide a sensitizer for high-intensity focused ultrasound (HIFU), where cavitation can be beneficial. While passive cavitation detection can accurately determine the pressure threshold, variations in acoustic impedance/backscatter from different nanoparticles can make it difficult to normalize the amount of cavitation and determine the precise magnitude of the physical consequences. Here we demonstrate a method to determine the extent of lysis of lipid membranes using liposomes loaded with a self-quenching fluorophore. Lysed liposomes released the fluorophore, causing an increase in the fluorescence signal. Liposomes were mixed with the nanoparticles and insonated with a HIFU transducer at physiological temperature. The pressure threshold for dye release was measured for a panel of nanoparticles. Nearly complete release of the dye was achievable in all cases, but it required higher pressures in the absence of nanoparticles. In addition, we measured the effect of a viscous medium, which is more representative of certain physiological states. Furthermore, the encapsulation of the nanoparticle within a liposome can create a platform delivery vehicle for anti-cancer therapeutics.
    The Journal of the Acoustical Society of America 10/2011; 130(4):2502. · 1.65 Impact Factor
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    ABSTRACT: The harmful side effects of chemotherapy originate from indiscriminate exposure of healthy tissue to the drugs. The goal of targeted drug delivery is to reduce these side effects by encapsulating concentrated drug in a vehicle which releases it only in the tumor region. Low intensity focused ultrasound can be used as a trigger to specifically activate these vehicles by highlighting only tumor tissue, creating a stark differentiation with healthy tissue. A new injectable drug delivery vehicle has been developed with a stabilized nested lipid shell geometry that encapsulates a high capacity chemotherapy payload, and a stabilized microbubble into one structure. Ultrasound affects the microbubble only in the small focal volume, creating a localized shockwave which ruptures the vehicle's outer membrane triggering pinpoint release in tissue phantoms. These shockwaves, and their interactions with the delivery vehicle membranes and live cells, have been documented for the first time using a custom system which combines high-speed videography and fluorescent microscopy with focused ultrasound. Vehicles which do not pass through the tumor will be excreted through normal processes. This externally-activated scheme could lead to truly tumor-specific drug delivery. [NCI Grant No. 5U54CA119335-05, and UCSD Cancer Center Specialized Support Grant No. P30 CA23100 supported this work.].
    The Journal of the Acoustical Society of America 10/2011; 130(4):2503. · 1.65 Impact Factor
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    ABSTRACT: The use of focused ultrasound can be an effective method to locally highlight tumor tissue and specifically trigger the activation of echogenic drug delivery vehicles in an effort to reduce systemic chemotherapy side effects. Here we demonstrate a unique ultrasound triggered vehicle design and fabrication method where the payload and a perfluorocarbon gas microbubble are both encapsulated within the internal aqueous space of a liposome. This nested lipid shell geometry both stabilized the microbubble and ensured it was spatially close enough to interact with the liposome membrane at all times. The internal microbubble was shown to fragment the outer liposome membrane upon exposure to ultrasound at intensities of 1-1.5MPa. The focused ultrasound allowed the release of the internal payload to localized regions within tissue phantoms. The vehicles showed high payload loading efficiency of 16%, stability in blood of several hours, and low level macrophage recognition in vitro. High speed fluorescent videos present the first optical images of such vehicles interacting with ultrasound. This ability to open the outer membrane in small regions of deep tissue could provide a second level of spatial and temporal control beyond biochemical targeting, making these particles promising for in vivo animal studies.
    Journal of Controlled Release 07/2011; 155(3):358-66. · 7.63 Impact Factor
  • Priya Prakash Karmali, Dmitri Simberg
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    ABSTRACT: INTRODUCTION: Intravenously injected nanoparticles, like any other foreign pathogen that enters the body, encounter multiple lines of defense intended to neutralize and eliminate the invading substance. Adsorption of plasma proteins on the nanoparticle surface is the first barrier of defense, which could lead to physical changes in the formulation, such as aggregation and charge neutralization, biochemical activation of defense cascades, and trigger elimination by multiple types of phagocytic cell. AREAS COVERED: In this review, recent knowledge on the mechanisms that govern the interactions of nanoparticles (micelles, liposomes, polymeric and inorganic nanoparticles) with plasma proteins is discussed. In particular, the role of the nanoparticle surface properties and protective polymer coating in these interactions is described. The mechanisms of protein adsorption on different nanoparticles are analyzed and the implications on the clearance, toxicity and efficacy of drug delivery are discussed. The review provides readers with the biological insight into the plasma/blood interactions of nanoparticles. EXPERT OPINION: The immune recognition of nanoparticles can seriously affect the drug delivery efficacy and toxicity. There is at present not enough knowledge on the mechanisms that dictate the nanoparticle immune recognition and stability in the biological milieu. Understanding the mechanisms of recognition will become an important part of nanoparticle design.
    Expert Opinion on Drug Delivery 03/2011; 8(3):343-57. · 4.87 Impact Factor
  • Dmitri Simberg, Robert Mattrey
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    ABSTRACT: Perfluorocarbon microbubbles (MBs) are routinely used as in vivo ultrasound contrast reagent. In addition, there is great interest in the use of MBs for ultrasound-mediated delivery, for example, of drugs and genes. As MB size (1-10 microm) limits their distribution to the vasculature, we aimed to assess the efficiency of targeting MBs to circulating cells using antibodies. Our experiments showed that MBs efficiently bind to erythrocytes and B-lymphoma cells in blood. The maximum binding was reached at a cell/MB ratio of 1:1. Following binding, the cells acquired buoyancy that allowed their easy separation from blood with brief centrifugation. Coating the MBs with DNA did not interfere with binding to cells. Experiments in mice showed that intravenously injected targeted MBs efficiently chased and bound to preinjected target cells in the bloodstream. Our data demonstrate the potential in targeting of blood cells for diagnostics and therapy.
    Journal of Drug Targeting 07/2009; 17(5):392-8. · 2.77 Impact Factor
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    ABSTRACT: Previously we reported that plasma kallikrein and high molecular weight kininogen attach to the surface of dextran-coated superparamagnetic iron oxide nanoparticles (SPION) through the incompletely covered iron oxide core (Simberg et al., Biomaterials, 2009). Here we show that SPION also activate kallikrein-kinin system in vitro and in vivo. The serine protease activity of kallikrein was stably associated with SPION and could be detected on the nanoparticles even after extensive washing steps. The enzymatic activity was not detectable in kininogen-deficient and Factor XII-deficient plasma. The enzymatic activation could be blocked by precoating SPION with histidine-rich Domain 5 (D5) of kininogen. Importantly, the kallikrein activity was detectable in plasma of SPION-injected, but not of D5/SPION-injected mice. Tumor-targeted SPION when injected into kininogen-deficient and control mice, produced high levels of vascular clotting in tumors, suggesting that kallikrein activation is not responsible for the nanoparticle-induced thrombosis. These data could help in understanding the toxicity of nanomaterials and could be used in designing nanoparticles with controlled enzymatic activity.
    Journal of Controlled Release 07/2009; 140(3):301-5. · 7.63 Impact Factor

Publication Stats

346 Citations
132.24 Total Impact Points

Institutions

  • 2014
    • University of Colorado
      • Skaggs School of Pharmacy and Pharmaceutical Sciences
      Denver, Colorado, United States
  • 2009–2014
    • University of California, San Diego
      • Moores Cancer Center/Oncology
      San Diego, California, United States
  • 2013
    • Julphar School of Pharmacy
      Denver, Colorado, United States
  • 2007–2012
    • Sanford-Burnham Medical Research Institute
      La Jolla, California, United States