Steven R Little

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (49)310.49 Total impact

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    ABSTRACT: Although approved by the United States Food and Drug Administration, enfuvirtide is rarely used in combination antiretroviral therapies (cART) to treat HIV-1 infection, primarily because of its intense dosing schedule that requires twice daily subcutaneous injection. Here, we describe the development of enfuvirtide-loaded, degradable poly(lactic-co-glycolic) acid microparticles that provide linear in vitro release of the drug over an 18 day period. This sustained release formulation could make enfuvirtide more attractive for use in cART.
    Antimicrobial Agents and Chemotherapy 12/2013; · 4.57 Impact Factor
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    ABSTRACT: The hallmark of periodontal disease is the progressive destruction of gingival soft tissue and alveolar bone, which is initiated by inflammation in response to an invasive and persistent bacterial insult. In recent years, it has become apparent that this tissue destruction is associated with a decrease in local regulatory processes, including a decrease of forkhead box P3-expressing regulatory lymphocytes. Accordingly, we developed a controlled release system capable of generating a steady release of a known chemoattractant for regulatory lymphocytes, C-C motif chemokine ligand 22 (CCL22), composed of a degradable polymer with a proven track record of clinical translation, poly(lactic-co-glycolic) acid. We have previously shown that this sustained presentation of CCL22 from a point source effectively recruits regulatory T cells (Tregs) to the site of injection. Following administration of the Treg-recruiting formulation to the gingivae in murine experimental periodontitis, we observed increases in hallmark Treg-associated anti-inflammatory molecules, a decrease of proinflammatory cytokines, and a marked reduction in alveolar bone resorption. Furthermore, application of the Treg-recruiting formulation (fabricated with human CCL22) in ligature-induced periodontitis in beagle dogs leads to reduced clinical measures of inflammation and less alveolar bone loss under severe inflammatory conditions in the presence of a diverse periodontopathogen milieu.
    Proceedings of the National Academy of Sciences 10/2013; · 9.74 Impact Factor
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    ABSTRACT: Glaucoma is the second leading cause of blindness in the United States. Brimonidine tartrate (BT) is a modern anti-glaucoma agent that is currently administered as frequently as a thrice-daily topical eye drop medication. Accordingly, compliance with BT regimens is low, limiting overall effectiveness. One attempt that has previously proven effective to address non-adherence is the formation of ocular inserts, such as the Ocusert ®, whose diffusion based control released an older drug (pilocarpine) for a week-long period. Modern controlled drug release technology provides an avenue for extending the release of practically any drug (including new drugs like BT) for as long as one month from a singular insert. Currently, no controlled release formulations for BT exist. This work outlines the development and characterization of a BT releasing ocular insert designed from poly (lactic co-glycolic) acid (PLGA)/poly ethylene glycol (PEG). We found that a formulation containing 15% PEG can be created that produces a linear BT release profile corresponding to BT eye drop delivery estimates. Additionally, these inserts were shown, through the use of atomic force microscopy and scanning electron microscopy, to have smooth surfaces and physical properties suitable for ophthalmic use.
    Acta biomaterialia 09/2013; · 5.09 Impact Factor
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    ABSTRACT: The shorter, the more dispersible: An iterative, emulsion-based shortening technique has been used to reduce the length of single-walled carbon nanotubes (SWNTs) to the same order of magnitude as their diameter (ca. 1 nm), thus achieving an effectively "zero-dimensional" structure with improved dispersibility and, after hydroxylation, long-term water solubility. Finally, zero-dimensional SWNTs were positively identified using mass spectrometry for the first time.
    Angewandte Chemie International Edition 09/2013; · 13.73 Impact Factor
  • Angewandte Chemie International Edition 09/2013; · 13.73 Impact Factor
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    ABSTRACT: Tregs play important roles in maintaining immune homeostasis, and thus, therapies based on Treg are promising candidates for the treatment for a variety of immune-mediated disorders. These therapies, however, face the significant challenge of obtaining adequate numbers of Tregs from peripheral blood that maintains suppressive function following extensive expansion. Inducing Tregs from non-Tregs offers a viable alternative. Different methods to induce Tregs have been proposed and involve mainly treating cells with TGF-β-iTreg. However, use of TGF-β alone is not sufficient to induce stable Tregs. ATRA or rapa has been shown to synergize with TGF-β to induce stable Tregs. Whereas TGF-β plus RA-iTregs have been well-described in the literature, the phenotype, function, and migratory characteristics of TGF-β plus rapa-iTreg have yet to be elucidated. Herein, we describe the phenotype and function of mouse rapa-iTreg and reveal that these cells differ in their in vivo homing capacity when compared with mouse RA-iTreg and mouse TGF-β-iTreg. This difference in migratory activity significantly affects the therapeutic capacity of each subset in a mouse model of colitis. We also describe the characteristics of iTreg generated in the presence of TGF-β, RA, and rapa.
    Journal of leukocyte biology 07/2013; · 4.99 Impact Factor
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    ABSTRACT: The development and performance evaluation of new biodegradable polymer controlled release formulations relies on successful interpretation and evaluation of in vitro release data. However, depending upon the extent of empirical characterization, release data may be open to more than one qualitative interpretation. In this work, a predictive model for release from degradable polymer matrices was applied to a number of published release data in order to extend the characterization of release behavior. Where possible, the model was also used to interpolate and extrapolate upon collected released data to clarify the overall duration of release and also kinetics of release between widely spaced data points. In each case examined, mathematical predictions of release coincide well with experimental results, offering a more definitive description of each formulation's performance than was previously available. This information may prove particularly helpful in the design of future studies, such as when calculating proper dosing levels or determining experimental end points in order to more comprehensively evaluate a controlled release system's performance.
    Molecular Pharmaceutics 09/2012; · 4.57 Impact Factor
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    ABSTRACT: The effect of sequence on copolymer properties is rarely studied despite the precedent from Nature that monomer order can create materials of significant diversity. Poly(lactic-co-glycolic acid) (PLGA), one of the most important biodegradable copolymers, is widely used in an unsequenced, random form for both drug delivery microparticles and tissue engineering matrices. Sequenced PLGA copolymers have been synthesized and fabricated into microparticles to study how their hydrolysis rates compare to those of random copolymers. Sequenced PLGA microparticles were found to degrade at slower, and often more constant, rates than random copolymers with the same lactic to glycolic acid ratios as demonstrated by molecular weight decrease, lactic acid release, and thermal property analyses. The impact of copolymer sequence on in vitro release was studied using PLGA microparticles loaded with model agent rhodamine-B. These assays established that copolymer sequence affects the rate of release and that a more gradual burst release can be achieved using sequenced copolymers compared to a random control.
    Journal of the American Chemical Society 09/2012; 134(39):16352-9. · 10.68 Impact Factor
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    ABSTRACT: A rationally designed controlled-release system is developed to recruit suppressive immune cells to specific sites in vivo. Continuous and sustained release of the chemokine CCL22 was achieved by fabricating porous polymeric microspheres. Application of these porous particles in vivo, in mice, leads to local regulatory T cell recruitment as well as a delay in rejection responses against transplanted allogeneic cells.
    Advanced Materials 07/2012; 24(35):4735-8. · 14.83 Impact Factor
  • Stephen C Balmert, Steven R Little
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    ABSTRACT: The nascent field of biomimetic delivery with micro- and nanoparticles (MNP) has advanced considerably in recent years. Drawing inspiration from the ways that cells communicate in the body, several different modes of "delivery" (i.e., temporospatial presentation of biological signals) have been investigated in a number of therapeutic contexts. In particular, this review focuses on (1) controlled release formulations that deliver natural soluble factors with physiologically relevant temporal context, (2) presentation of surface-bound ligands to cells, with spatial organization of ligands ranging from isotropic to dynamically anisotropic, and (3) physical properties of particles, including size, shape and mechanical stiffness, which mimic those of natural cells. Importantly, the context provided by multimodal, or multifactor delivery represents a key element of most biomimetic MNP systems, a concept illustrated by an analogy to human interpersonal communication. Regulatory implications of increasingly sophisticated and "cell-like" biomimetic MNP systems are also discussed.
    Advanced Materials 04/2012; 24(28):3757-78. · 14.83 Impact Factor
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    ABSTRACT: The application of porous hollow fibers has recently been extended to the controlled release of biologics such as protein growth factors and lipid angiogenesis promoters. Release of these materials tends to occur more rapidly than would be predicted by conventional diffusion-based models of controlled release. Analysis of other modalities of transport as well as structural analysis of the controlled release system itself was performed to provide insight into the observed controlled release behavior from such systems. Specifically, it was discovered that osmotic-driven processes play a significant role in controlled release of proteins including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). It was also found that the fiber pore microstructure and (more importantly) macrostructure influences release behavior. Model-guided design was implemented to adjust the physical properties of the fiber wall, leading to a release system that is better able to sustain the delivery of VEGF. This model may be used to more easily achieve a desired complex release behavior when used in combination with external regulation of the reservoir.
    Journal of Biomedical Materials Research Part A 03/2012; 100(4):817-26. · 2.83 Impact Factor
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    Steven R Little
    Proceedings of the National Academy of Sciences 01/2012; 109(4):999-1000. · 9.74 Impact Factor
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    ABSTRACT: The absence of regulatory T cells (Treg) is a hallmark for a wide variety of disorders such as autoimmunity, dermatitis, periodontitis and even transplant rejection. A potential treatment option for these disorders is to increase local Treg numbers. Enhancing local numbers of Treg through in situ Treg expansion or induction could be a potential treatment option for these disorders. Current methods for in vivo Treg expansion rely on biologic therapies, which are not Treg-specific and are associated with many adverse side-effects. Synthetic formulations capable of inducing Treg could be an alternative strategy to achieve in situ increase in Treg numbers. Here we report the development and in vitro testing of a Treg-inducing synthetic formulation that consists of controlled release vehicles for IL-2, TGF-β and rapamycin (a combination of cytokines and drugs that have previously been reported to induce Treg). We demonstrate that IL-2, TGF-β and rapamycin (rapa) are released over 3-4weeks from these formulations. Additionally, Treg induced in the presence of these formulations expressed the canonical markers for Treg (phenotype) and suppressed naïve T cell proliferation (function) at levels similar to soluble factor induced Treg as well as naturally occurring Treg. Most importantly, we show that these release formulations are capable of inducing FoxP3(+) Treg in human cells in vitro. In conclusion, our data suggest that controlled release formulations of IL-2, TGF-β and rapa can induce functional Treg in vitro with the potential to be developed into an in vivo Treg induction and expansion therapy.
    Journal of Controlled Release 01/2012; 159(1):78-84. · 7.63 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Therapeutic gene replacement of a dystrophin cDNA into dystrophic muscle can provide functional dystrophin protein to the tissue. However, vector-mediated gene transfer is limited by anti-vector and anti-transgene host immunity that causes rejection of the therapeutic protein. We hypothesized that rapamycin (RAPA) would diminish immunity due to vector-delivered recombinant dystrophin in the adult mdx mouse model for DMD. To test this hypothesis, we injected limb muscle of mdx mice with RAPA-containing, poly-lactic-co-glycolic acid (PLGA) microparticles prior to dystrophin gene transfer and analyzed treated tissue after 6 weeks. RAPA decreased host immunity against vector-mediated dystrophin protein, as demonstrated by decreased cellular infiltrates and decreased anti-dystrophin antibody production. The interpretation of the effect of RAPA on recombinant dystrophin expression was complex because of an effect of PLGA microparticles.
    Scientific Reports 01/2012; 2:399. · 2.93 Impact Factor
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    ABSTRACT: Via Dissipative Particle Dynamics (DPD) approach, we study the spontaneous insertion of amphiphilic nanotubes into a lipid vesicle, which is immersed in a hydrophilic solvent. Individual lipids are composed of a hydrophilic head group and two hydrophobic tails. Each nanotube encompasses an ABA architecture, with a hydrophobic shaft (B) and two hydrophilic ends (A). To facilitate the selective transport of species through the nanotubes, we introduce hydrophilic tethers at one end of the tube. We show that nanotubes initially located in the host solvent spontaneously penetrate the vesicle's membrane and assume a transmembrane position, with the hydrophilic tethers extending from the surface of the vesicle. Adding nanotubes one at a time after the previous nanotube has been inserted, we characterize the interactions among the nanotubes that have self-assembled into the vesicle's membrane and focus on their clustering within the membrane. We also show that the nanotube insertion and clustering within the vesicle strongly affects the vesicle shape in cases of a sufficiently large number of tubes. Ultimately, these nanotube-lipid systems can be used for creating hybrid controlled release vesicles.
    Current Nanoscience 09/2011; 7(5):699-715. · 1.36 Impact Factor
  • Angewandte Chemie International Edition 08/2011; 50(37):8706-8. · 13.73 Impact Factor
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    Siddharth Jhunjhunwala, Steven R Little
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    ABSTRACT: Comment on: Jhunjhunwala S, et al. J Control Release 2009;133:191-7.
    Cell cycle (Georgetown, Tex.) 07/2011; 10(13):2047-8. · 5.24 Impact Factor
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    ABSTRACT: Via dissipative particle dynamics (DPD), we simulate the self-assembly of end-functionalized, amphiphilic nanotubes and lipids in a hydrophilic solvent. Each nanotube encompasses a hydrophobic stalk and two hydrophilic ends, which are functionalized with end-tethered chains. With a relatively low number of the nanotubes in solution, the components self-assemble into stable lipid-nanotube vesicles. As the number of nanotubes is increased, the system exhibits a vesicle-to-bicelle transition, resulting in stable hybrid bicelle. Moreover, our results reveal that the nanotubes cluster into distinct tripod-like structures within the vesicles and aggregate into a ring-like assembly within the bicelles. For both the vesicles and bicelles, the nanotubes assume trans-membrane orientations, with the tethered hairs extending into the surrounding solution or the encapsulated fluid. Thus, the hairs provide a means of regulating the transport of species through the self-assembled structures. Our findings provide guidelines for creating nanotube clusters with distinctive morphologies that might be difficult to achieve through more conventional means. The results also yield design rules for creating synthetic cell-like objects or microreactors that can exhibit biomimetic functionality.
    ACS Nano 05/2011; 5(6):4769-82. · 12.06 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked, lethal, degenerative disease that results from mutations in the dystrophin gene, causing necrosis and inflammation in skeletal muscle tissue. Treatments that reduce muscle fiber destruction and immune cell infiltration can ameliorate DMD pathology. We treated the mdx mouse, a model for DMD, with the immunosuppressant drug rapamycin (RAPA) both locally and systemically to examine its effects on dystrophic mdx muscles. We observed a significant reduction of muscle fiber necrosis in treated mdx mouse tibialis anterior (TA) and diaphragm (Dia) muscles 6 wks post-treatment. This effect was associated with a significant reduction in infiltration of effector CD4(+) and CD8(+) T cells in skeletal muscle tissue, while Foxp3(+) regulatory T cells were preserved. Because RAPA exerts its effects through the mammalian target of RAPA (mTOR), we studied the activation of mTOR in mdx TA and Dia with and without RAPA treatment. Surprisingly, mTOR activation levels in mdx TA were not different from control C57BL/10 (B10). However, mTOR activation was different in Dia between mdx and B10; mTOR activation levels did not rise between 6 and 12 wks of age in mdx Dia muscle, whereas a rise in mTOR activation level was observed in B10 Dia muscle. Furthermore, mdx Dia, but not TA, muscle mTOR activation was responsive to RAPA treatment.
    Molecular Medicine 05/2011; 17(9-10):917-24. · 4.47 Impact Factor
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    ABSTRACT: An externally regulated delivery model that permits temporal separation of multiple angiogenic factors was used for the delivery of basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). While bFGF plays a significant role in the sprouting of new capillaries, PDGF plays a role in the recruitment of mural cells, which stabilize neovessels. However, these two factors have been shown to inhibit each other, when presented together. Using the externally regulated model, sequential delivery of bFGF and PDGF led to not only increased endothelial cell migration, but also endothelial cell and vascular pericyte colocalization. More importantly, this delivery strategy was able to induce red blood cell-filled neovessels, suggesting integration of angiogenesis with the existing vasculature.
    Tissue Engineering Part A 01/2011; 17(9-10):1181-9. · 4.64 Impact Factor

Publication Stats

743 Citations
177 Downloads
3k Views
310.49 Total Impact Points

Institutions

  • 2006–2013
    • University of Pittsburgh
      • • Chemical and Petroleum Engineering
      • • Bioengineering
      Pittsburgh, Pennsylvania, United States
  • 2005–2010
    • Northeastern University
      • Department of Pharmaceutical Sciences
      Boston, MA, United States
  • 2008
    • Massachusetts General Hospital
      • Department of Orthopaedic Surgery
      Boston, MA, United States
  • 2004–2007
    • Massachusetts Institute of Technology
      • Department of Chemical Engineering
      Cambridge, Massachusetts, United States