Krishnendu Roy

University of Texas at Austin, Austin, Texas, United States

Are you Krishnendu Roy?

Claim your profile

Publications (54)257.22 Total impact

  • Jardin Leleux · Alexandra Atalis · Krishnendu Roy ·
    [Show abstract] [Hide abstract]
    ABSTRACT: While successful vaccines have been developed against many pathogens, there are still many diseases and pathogenic infections that are highly evasive to current vaccination strategies. Thus, more sophisticated approaches to control the type and quality of vaccine-induced immune response must be developed. Dendritic cells (DCs) are the sentinels of the body and play a critical role in immune response generation and direction by bridging innate and adaptive immunity. It is now well recognized that DCs can be separated into many subgroups, each of which has a unique function. Better understanding of how various DC subsets, in lymphoid organs and in the periphery, can be targeted through controlled delivery; and how these subsets modulate and control the resulting immune response could greatly enhance our ability to develop new, effective vaccines against complex diseases. In this review, we provide an overview of DC subset biology and discuss current immunotherapeutic strategies that utilize DC targeting to modulate and control immune responses.
    Journal of Controlled Release 10/2015; 219. DOI:10.1016/j.jconrel.2015.09.063 · 7.71 Impact Factor
  • Patrick Jurney · Rachit Agarwal · Krishnendu Roy · S V Sreenivasan · Li Shi ·

    Journal of Nanotechnology in Engineering and Medicine 10/2015; DOI:10.1115/1.4031856
  • [Show abstract] [Hide abstract]
    ABSTRACT: Efficient penetration and uniform distribution of nanoparticles (NPs) inside solid tissues and tumors is paramount to their therapeutic and diagnostic success. While many studies have reported the effect of NP size and charge on intratissue distribution, role of shape, and aspect ratio on NP transport inside solid tissues remain unclear. Here experimental and theoretical studies are reported on how nanoscale geometry of Jet and Flash Imprint Lithography-fabricated, polyethylene-glycol-based anionic nanohydrogels affect their penetration and distribution inside 3D spheroids, a model representing the intervascular region of solid, tumor-like tissues. Unexpectedly, low aspect ratio cylindrical NPs (H/D ≈0.3; disk-like particles, 100 nm height, and 325 nm diameter) show maximal intratissue delivery (>50% increase in total cargo delivered) and more uniform penetration compared to nanorods or smaller NPs of the same shape. This is in contrast to spherical NPs where smaller NP size resulted in deeper, more uniform penetration. Our results provide fundamental new knowledge on NP transport inside solid tissues and further establish shape and aspect ratio as important design parameters in developing more efficient, better penetrating, nanocarriers for drug, or contrast-agent delivery.
    Advanced Healthcare Materials 09/2015; 4(15). DOI:10.1002/adhm.201500441 · 5.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new process, decoupled functional imprint lithography (D-FIL), is presented for fabricating low elastic modulus polymeric nanocarriers possessing Young's modulus of bulk material as low as sub-1 MPa. This method is employed to fabricate sub-50 nm diameter cylinders with >3:1 aspect ratio and other challenging shapes from low elastic modulus polymers such as N-isopropylacrylamide (NIPAM) and poly(ethylene glycol) di-acrylate (PEGDA), possessing Young's modulus of bulk material <10 MPa which is cannot otherwise be imprinted in similar size and pitch using existing imprint techniques. Standard imprint lithography polymers have Young's modulus >1 GPa, and so these polymers used in nanocarrier fabrication in comparison have very low elastic modulus. Monodispersed, shape- and size-specific nanocarriers composed of NIPAM with material elastic modulus of <1 MPa have been fabricated and show thermal responsive behavior at the lower critical solubility temperature (LCST) of ∼32 °C. In addition, re-entrant shaped nanocarriers composed of PEGDA with elastic modulus <10 MPa are also fabricated. Nanocarriers fabricated from PEGDA are shown with model imaging agent and anticancer drug (Doxorubicin) encapsulated in as small as 50 nm cylindrical nanocarriers.
    03/2015; 3(1-1):011002-011002. DOI:10.1115/1.4028896
  • [Show abstract] [Hide abstract]
    ABSTRACT: Success of an immunotherapy for cancer often depends on the critical balance of T helper 1 (Th1) and T helper 2 (Th2) responses driven by antigen presenting cells, specifically dendritic cells (DCs). Th1-driven cytotoxic T cell (CTL) responses are key to eliminating tumor cells. It is well established that CpG oligonucleotides (ODN), a widely studied Toll-like receptor 9 (TLR9) agonist, used to enhance Th1 response, also induces high levels of the anti-inflammatory, Th2-promoting cytokine IL10, which could dampen the resulting Th1 response. Biomaterials-based immunomodulatory strategies that can reduce IL10 production while maintaining IL12 levels during CpG delivery could further enhance the Th1/Th2 cytokine balance and improve anti-tumor immune response. Here we report that dual-delivery of IL10-silencing siRNA along with CpG ODN to the same DCs using pathogen-mimicking microparticles (PMPs), significantly enhances their Th1/Th2 cytokine ratio through concurrent inhibition of CpG-induced IL10 production. Co-delivery of poly(I:C), a TLR3 agonist had only minor effects on IL10 levels. Further, simultaneous immunotherapy with CpG ODN and IL10 siRNA enhanced immune protection of an idiotype DNA vaccine in a prophylactic murine model of B cell lymphoma whereas co-delivery of poly(I:C) and CpG did not enhance protection. These results suggest that PMPs can be used to precisely modulate TLR ligand-mediated immune-stimulation in DCs, through co-delivery of cytokine-silencing siRNAs and thereby boost antitumor immunity.
    Biomaterials 04/2014; 35(21). DOI:10.1016/j.biomaterials.2014.03.039 · 8.56 Impact Factor
  • Source
    Irina Fernandez · Tracy P Ooi · Krishnendu Roy ·
    [Show abstract] [Hide abstract]
    ABSTRACT: In vitro differentiation of mouse and human stem cells into early T cells has been successfully demonstrated using artificial Notch signaling systems. However, generation of mature, antigen-specific, functional T cells, directly from human stem cells has remained elusive, except when using stromal co-culture of stem cells retrovirally transfected with antigen-specific T cell receptors (TCRs). Here we show that human umbilical cord blood (UCB)-derived CD34+CD38-/low hematopoietic stem cells (HSCs) can be successfully differentiated into functional, antigen-specific cytotoxic CD8+ T cells without direct stromal co-culture or retroviral TCR transfection. Surface-immobilized Notch ligands (DLL1) and stromal cell conditioned medium successfully induced the development of CD1a+CD7+ and CD4+CD8+ early T cells. These cells, upon continued culture with cytomegalovirus (CMV) or Influenza-A virus epitope-loaded HLA-A*0201 tetramers, resulted in the generation of a polyclonal population of CMV-specific or Influenza-specific CD8+ T cells respectively. Upon further activation with antigen-loaded target cells, these antigen-specific, stem cell-derived T cells exhibited cytolytic functionality, specifically CD107a surface mobilization, IFNγ production, and Granzyme B secretion. Such scalable, in vitro generation of functional, antigen-specific human T cells from human stem cells could eventually provide a readily available cell source for adoptive transfer immunotherapies and also allow better understanding of human T cell development. Stem Cells 2013.
    Stem Cells 01/2014; 32(1). DOI:10.1002/stem.1512 · 6.52 Impact Factor
  • Alberto Purwada · Krishnendu Roy · Ankur Singh ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Controlled modulation of immune response, especially the balance between immunostimulatory and immunosuppressive responses is critical for a variety of clinical applications, including immunotherapies against cancer and infectious diseases, treatment of autoimmune disorders, transplant surgeries, regenerative medicine, prosthetic implants etc. Our ability to precisely modify both innate and adaptive immune responses could provide new therapeutic directions in a variety of diseases. In the context of vaccines and immunotherapies, the interplay between antigen presenting cells (e.g. dendritic cells and macrophages), B cells, T helper and killer subtypes, and regulatory T and B cell responses is critical for generating effective immunity against cancer, infectious diseases, and autoimmune diseases. In recent years, immunoengineering has emerged as a new field that uses quantitative engineering tools to understand molecular, cellular and systems-level interactions of the immune system and develop design-driven approaches to control and modulate immune-responses. Biomaterials are an integral part of this engineering tool-box and can exploit the intrinsic biological and mechanical cues of the immune system to directly modulate and train immune cells and direct their response to a particular phenotype. A large body of literature exists on strategies to evade or suppress the immune response in implants, transplantation and regenerative medicine, and has been discussed in several excellent reviews [1,2]. This review specifically focuses on the use of biomaterials for immunostimulation and controlled modulation, especially in the context of vaccines and immunotherapies against cancer, infectious diseases and autoimmune disorders. Bioengineering smart systems that can simultaneously deliver multiple bioactive agents in a controlled manner or can work as a niche for in situ priming and modulation of the immune system could significantly enhance the efficacy of next generation immunotherapeutics. In this review, we describe our perspective on the important design aspects for the development of biomaterials that can actively modulate immune responses by stimulating receptor complexes, cells, and delivering multiple immunomodulatory biomolecules.
    Acta biomaterialia 12/2013; 10(4). DOI:10.1016/j.actbio.2013.12.036 · 6.03 Impact Factor
  • Ankur Singh · Pallab Pradhan · Krishnendu Roy ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Vaccines have been one of the most important discoveries of modern medicine. They are the primary mode of protection against a wide range of infectious diseases and, if effective, can provide long-lasting immunity. Despite recent advances in our understanding of the immune system, prophylactic vaccines against chronic infectious diseases and immunotherapeutic vaccines against cancer remain elusive. Unlike preventive vaccines that have virtually eradicated fatal diseases like polio and smallpox, immunotherapy of chronic diseases and established or unexpected infections, for example human immunodeficiency virus (HIV), has yet to demonstrate global clinical success. Even for diseases where preventive vaccines are available, for example influenza, the protection is transient and requires multiple administration and yearly immunizations. In addition, most cancers and emerging infectious diseases, like the H1N1 influenza, and drug resistance infections like tuberculosis, need new transformative strategies to increase protective immunity many folds over currently available vaccines. Successful immunotherapy using vaccines requires effective strategies to penetrate tissue barriers, efficiently target antigens, adjuvants and immune-modulators to immune surveillance cells, provide strong stimulatory effects to activate those cells, and modulate the cellular response appropriately and efficiently in order to generate potent antiviral or anticancer immunity. The emerging field of immunobioengineering provides new concepts and strategies to design materials, antigens, and adjuvants to induce potent immune response; and engineer vaccine delivery systems to modulate the behavior of immune cells [1]. In this chapter we review the state-of-the-art approaches in immunobioengineering with specific focus on delivery formulations for multiple immune-modulators and antigens. © 2013 Springer Science+Business Media New York. All rights are reserved.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Size, surface charge, and material compositions are known to influence cell uptake of nanoparticles. However, the effect of particle geometry, i.e., the interplay between nanoscale shape and size, is less understood. Here we show that when shape is decoupled from volume, charge, and material composition, under typical in vitro conditions, mammalian epithelial and immune cells preferentially internalize disc-shaped, negatively charged hydrophilic nanoparticles of high aspect ratios compared with nanorods and lower aspect-ratio nanodiscs. Endothelial cells also prefer nanodiscs, however those of intermediate aspect ratio. Interestingly, unlike nanospheres, larger-sized hydrogel nanodiscs and nanorods are internalized more efficiently than their smallest counterparts. Kinetics, efficiency, and mechanisms of uptake are all shape-dependent and cell type-specific. Although macropinocytosis is used by both epithelial and endothelial cells, epithelial cells uniquely internalize these nanoparticles using the caveolae-mediated pathway. Human umbilical vein endothelial cells, on the other hand, use clathrin-mediated uptake for all shapes and show significantly higher uptake efficiency compared with epithelial cells. Using results from both upright and inverted cultures, we propose that nanoparticle internalization is a complex manifestation of three shape- and size-dependent parameters: particle surface-to-cell membrane contact area, i.e., particle-cell adhesion, strain energy for membrane deformation, and sedimentation or local particle concentration at the cell membrane. These studies provide a fundamental understanding on how nanoparticle uptake in different mammalian cells is influenced by the nanoscale geometry and is critical for designing improved nanocarriers and predicting nanomaterial toxicity.
    Proceedings of the National Academy of Sciences 10/2013; 110(43). DOI:10.1073/pnas.1305000110 · 9.67 Impact Factor

  • Journal of Nanotechnology in Engineering and Medicine 08/2013; 4(3):031002. DOI:10.1115/1.4025609
  • Rachit Agarwal · Krishnendu Roy ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent progress in drug discovery has enabled the targeting of specific intracellular molecules to achieve therapeutic effects. These next-generation therapeutics are often biologics that cannot enter cells by mere diffusion. Therefore, it is imperative that drug carriers are efficiently internalized by cells and reach specific target organelles before releasing their cargo. Nanoscale polymeric carriers are particularly suitable for such intracellular delivery. Although size and surface charge have been the most studied parameters for nanocarriers, it is now well appreciated that other properties, for example, particle shape, elasticity and surface composition, also play a critical role in their transport across physiological barriers. It is proposed that a multivariate design space that considers the interdependence of particle geometry with its mechanical and surface properties must be optimized to formulate drug nanocarriers for effective accumulation at target sites and efficient intracellular delivery.
    Therapeutic delivery 06/2013; 4(6):705-23. DOI:10.4155/tde.13.37
  • Jardin Leleux · Krishnendu Roy ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The development and widespread application of vaccines has been one of the most significant achievements of modern medicine. Vaccines have not only been instrumental in controlling and even eliminating life-threatening diseases like polio, measles, diphtheria, etc., but have also been immensely powerful in enhancing the worldwide outlook of public health over the past century. Despite these successes, there are still many complex disorders (e.g., cancer, HIV, and other emerging infectious diseases) for which effective preventative or therapeutic vaccines have been difficult to develop. This failure can be attributed primarily to our inability to precisely control and modulate the highly complex immune memory response, specifically the cellular response. Dominated by B and T cell maturation and function, the cellular response is primarily initiated by potent immunostimulators and antigens. Efficient and targeted delivery of these immunomodulatory and immunostimulatory molecules to appropriate cells is key to successful development of next generation vaccine formulations. Over the past decade, particulate carriers have emerged as an attractive means for enhancing the delivery efficacy and potency of vaccines and associated immunomodulatory molecules. Specifically, polymer-based micro and nanoparticles are being extensively studied for a wide variety of applications. In this review, we discuss the immunological fundamentals for developing effective vaccines and how materials and material properties can be exploited to improve these therapies. Particular emphasis is given to polymer-based particles and how the route of administration of particulate systems affects the phenotype and robustness of an immune response. Comparison of various strategies and recent advancements in the field are discussed along with insights into current limitations and future directions.
    01/2013; 2(1). DOI:10.1002/adhm.201200268
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In vitro bioreactor-based cultures are being extensively investigated for large-scale production of differentiated cells from embryonic stem cells (ESCs). However, it is unclear whether in vitro ESC-derived progenitors have similar gene expression profiles and functionalities as their in vivo counterparts. This is crucial in establishing the validity of ESC-derived cells as replacements for adult-isolated cells for clinical therapies. In this study, we compared the gene expression profiles of Lin-ckit+Sca-1+ (LKS) cells generated in vitro from mouse ESCs using either static or bioreactor-based cultures, with that of native LKS cells isolated from mouse fetal liver (FL) or bone marrow (BM). We found that in vitro-generated LKS cells were more similar to FL- than to BM LKS cells in gene expression. Further, when compared to cells derived from bioreactor cultures, static culture-derived LKS cells showed fewer differentially expressed genes relative to both in vivo LKS populations. Overall, the expression of hematopoietic genes was lower in ESC-derived LKS cells compared to cells from BM and FL, while the levels of non-hematopoietic genes were up-regulated. In order to determine if these molecular profiles correlated with functionality, we evaluated ESC-derived LKS cells for in vitro hematopoietic-differentiation and colony formation (CFU assay). Although static culture-generated cells failed to form any colonies, they did differentiate into CD11c+ and B220+ cells indicating some hematopoietic potential. In contrast, bioreactor-derived LKS cells, when differentiated under the same conditions failed to produce any B220+ or CD11c+ cells and did not form colonies, indicating that these cells are not hematopoietic progenitors. We conclude that in vitro culture conditions significantly affect the transcriptome and functionality of ESC-derived LKS cells and although in vitro differentiated LKS cells were lineage negative and expressed both ckit and Sca-1, these cells, especially those obtained from dynamic cultures, are significantly different from native cells of the same phenotype.
    PLoS ONE 12/2012; 7(12):e51944. DOI:10.1371/journal.pone.0051944 · 3.23 Impact Factor
  • Prinda Wanakule · Gary W Liu · Asha T Fleury · Krishnendu Roy ·
    [Show abstract] [Hide abstract]
    ABSTRACT: It is well appreciated that delivery of therapeutic agents through the pulmonary route could provide significant improvement in patient compliance and reduce systemic toxicity for a variety of diseases. Many inhalable drug formulations suffer from low respirable fractions, rapid clearance by alveolar macrophages, target non-specificity, and difficulty in combining aerodynamic properties with efficient cellular uptake. To overcome these challenges, we developed an enzyme-responsive, nanoparticle-in-microgel delivery system. This system is designed to provide optimal aerodynamic carrier size for deep lung delivery, improved residence time of carriers in the lungs by avoiding rapid clearance by macrophages, and reduction of side effects and toxicity by releasing encapsulated therapeutics in response to disease-specific stimuli. This unique carrier system is fabricated using a new Michael addition during (water-in-oil) emulsion (MADE) method, especially suitable for biologic drugs due to its gentle fabrication conditions. The resulting microgels have a highly porous internal structure and an optimal aerodynamic diameter for effective deep lung delivery. They also exhibit triggered release of various nanoparticles and biologics in the presence of physiological levels of enzyme. In addition, the nanoparticle-carrying microgels showed little uptake by macrophages, indicating potential for increased lung residence time and minimal clearance by alveolar macrophages. Collectively, this system introduces a rationally designed, disease-specific, multi-tiered delivery system for use as an improved pulmonary carrier for biologic drugs.
    Journal of Controlled Release 07/2012; 162(2):429-37. DOI:10.1016/j.jconrel.2012.07.026 · 7.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intravenous injection of nanoparticles as drug delivery vehicles is a common practice used in in-vivo and clinical trials of therapeutic agents to target specific cancerous or pathogenic sites. The vascular flow dynamics of nanocarriers in human capillaries play an important role in the ultimate efficacy of this drug delivery method. This article reports an experimental study of the effect of nanoparticle size on their margination and adhesion propensity in micro fabricated microfluidic channels of a half elliptical cross-section. Spherical polystyrene particles ranging in diameter from 60 to 970 nm were flown in the microchannels and individual particles adhered to either the channel’s top or bottom wall were imaged using fluorescence microscopy. The results show a significant increase in adhesion for particles with diameter below 200 nm as well as the emergence of a critical nanoparticle diameter of about 970 nm, where no nanoparticle adherence was observed on the top wall. For the same particle number concentration, the total volume of the nanoparticles adhered to the top and bottom walls was found to increase with decreasing diameter for diameters less than 200 nm. The results are explained by the competition between Brownian motion, gravity and hemodynamic forces on the nanoparticles. These findings on the flow behavior of spherical nanoparticles in artificial micro-capillaries provide further insight for the rational design of nanocarriers for targeted cancer therapeutics.
    ASME 2012 Third International Conference on Micro/Nanoscale Heat and Mass Transfer; 03/2012
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing interest in fabricating shape-specific polymeric nano- and microparticles for efficient delivery of drugs and imaging agents. The size and shape of these particles could significantly influence their transport properties and play an important role in in vivo biodistribution, targeting, and cellular uptake. Nanoimprint lithography methods, such as jet-and-flash imprint lithography (J-FIL), provide versatile top-down processes to fabricate shape-specific, biocompatible nanoscale hydrogels that can deliver therapeutic and diagnostic molecules in response to disease-specific cues. However, the key challenges in top-down fabrication of such nanocarriers are scalable imprinting with biological and biocompatible materials, ease of particle-surface modification using both aqueous and organic chemistry as well as simple yet biocompatible harvesting. Here we report that a biopolymer-based sacrificial release layer in combination with improved nanocarrier-material formulation can address these challenges. The sacrificial layer improves scalability and ease of imprint-surface modification due to its switchable solubility through simple ion exchange between monovalent and divalent cations. This process enables large-scale bionanoimprinting and efficient, one-step harvesting of hydrogel nanoparticles in both water- and organic-based imprint solutions.
    ACS Nano 03/2012; 6(3):2524-31. DOI:10.1021/nn2049152 · 12.88 Impact Factor
  • Prinda Wanakule · Krishnendu Roy ·
    [Show abstract] [Hide abstract]
    ABSTRACT: With the advent of highly potent and cytotoxic drugs, it is increasingly critical that they be targeted and released only in cells of diseased tissues, while sparing physiologically normal neighbors. Simple ligand-based targeting of drug carriers, although promising, cannot always provide the required specificity to achieve this since often normal cells also express significant levels of the targeted receptors. Therefore, stimuli-responsive delivery systems are being explored to allow drug release from nano- and microcarriers and implantable devices, primarily in the presence of physiological or disease-specific pathophysiological signals. Designing smart biomaterials that respond to temperature or pH changes, protein and ligand binding, disease-specific degradation, e.g. enzymatic cleavage, has become an integral part of this approach. These strategies are used in combination with nano- and microparticle systems to improve delivery efficiency through several routes of administration, and with injectable or implantable systems for long term controlled release. This review focuses on recent developments in stimuli-responsive systems, their physicochemical properties, release profiles, efficacy, safety and biocompatibility, as well as future perspectives.
    Current Drug Metabolism 01/2012; 13(1):42-9. DOI:10.2174/138920012798356880 · 2.98 Impact Factor
  • Lonnissa H Nguyen · Abhijith K Kudva · Neha S Saxena · Krishnendu Roy ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite significant advances in stem cell differentiation and tissue engineering, directing progenitor cells into three-dimensionally (3D) organized, native-like complex structures with spatially-varying mechanical properties and extra-cellular matrix (ECM) composition has not yet been achieved. The key innovations needed to achieve this would involve methods for directing a single stem cell population into multiple, spatially distinct phenotypes or lineages within a 3D scaffold structure. We have previously shown that specific combinations of natural and synthetic biomaterials can direct marrow-derived stem cells (MSC) into varying phenotypes of chondrocytes that resemble cells from the superficial, transitional, and deep zones of articular cartilage. In this current study, we demonstrate that layer-by-layer organization of these specific biomaterial compositions creates 3D niches that allow a single MSC population to differentiate into zone-specific chondrocytes and organize into a complex tissue structure. Our results indicate that a three-layer polyethylene glycol (PEG)-based hydrogel with chondroitin sulfate (CS) and matrix metalloproteinase-sensitive peptides (MMP-pep) incorporated into the top layer (superficial zone, PEG:CS:MMP-pep), CS incorporated into the middle layer (transitional zone, PEG:CS) and hyaluronic acid incorporated in the bottom layer (deep zone, PEG:HA), creates native-like articular cartilage with spatially-varying mechanical and biochemical properties. Specifically, collagen II levels decreased gradually from the superficial to the deep zone, while collagen X and proteoglycan levels increased, leading to an increasing gradient of compressive modulus from the superficial to the deep zone. We conclude that spatially-varying biomaterial compositions within single 3D scaffolds can stimulate efficient regeneration of multi-layered complex tissues from a single stem cell population.
    Biomaterials 06/2011; 32(29):6946-52. DOI:10.1016/j.biomaterials.2011.06.014 · 8.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with malignant non-Hodgkin's lymphomas (NHL) of B-cell lineages relapse despite initial anti-tumor response to chemotherapy or antibody treatments. Failure to eliminate the tumor is often because of inadequate priming, low cell numbers and suboptimal phenotype of effector T cells. Here we describe a new biomaterial-based controlled-release paradigm to treat weakly immunogenic NHLs by in-situ amplifying the number of functional, antigen-specific T-helper 1 (Th1) cells following immunotherapy. An injectable, synthetic immune priming center (sIPC) consisting of an in-situ crosslinking, chemokine-carrying hydrogel and both DNA- and siRNA dual-loaded microparticles, is reported. This sIPC chemo attracts a large number of immature dendritic cells (DCs) at the site of administration and efficiently co-delivers both DNA antigens and interleukin-10 (IL10)-silencing siRNA to those cells. Using a murine model of A20 B cell lymphoma, we demonstrate that combination of DNA-antigen delivery and IL10 silencing, synergistically activate recruited immature DCs and cause a strong shift towards Th1 response while suppressing Th2 and Th17 cytokines. sIPC-based immunotherapy showed 45% more CD8+ cytotoxic T cell (CTL) response and 53% stronger CD4+ CTL activity compared to naked DNA vaccine. In addition, in-vivo sIPC immunization induced significant protection (p<0.01) against subsequent tumor challenge. Such a multi-modal, injectable system that simultaneously delivers chemokines, siRNA and DNA antigens to DCs marks a new approach to in-situ priming and modulation during immunotherapy and could provide effective vaccination strategies against cancers and infectious diseases.
    Journal of Controlled Release 06/2011; 155(2):184-92. DOI:10.1016/j.jconrel.2011.06.008 · 7.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently a number of hydrogel-based micro-and nanoscale drug carriers have been reported including top down fabricated, highly monodisperse nanoparticles of specific sizes and shapes. One critical question on such approaches is whether in vivo swelling of the nanoparticles could considerably alter their geometry to a point where the potential benefit of controlling size or shape could not be realized. Little has been reported on experimental characterization of the swelling behavior of nanoscale hydrogel structures, and current theoretical understanding is largely based on bulk hydrogel systems. Using atomic force microscopy (AFM) and environmental scanning electron microscopy (ESEM) capsules, we have characterized the swelling behavior of nano-imprinted hydrogel particles of different sizes and aspect ratios. Our results indicate a size-dependent swelling which can be attributed to the effect of substrate constraint of as-fabricated particles, when the particles are still attached to the imprinting substrate. Numerical simulations based on a recently developed field theory and a nonlinear finite element method were conducted to illustrate the constraint effect on swelling and drying behavior of substrate-supported hydrogel particles of specific geometries, and compared closely with experimental measurements. Further, we present a theoretical model that predicts the size-dependent swelling behavior for unconstrained sub-micron hydrogel particles due to the effect of surface tension. Both experimental and theoretical results suggest that hydrogel swelling does not significantly alter the shape and size of highly crosslinked nanoscale hydrogel particles used in the present study.
    Soft Matter 03/2011; 7(6). DOI:10.1039/C0SM01185A · 4.03 Impact Factor