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Oral IL-10 Gene Delivery in a Microsphere-Based Formulation for Local Transfection and Therapeutic Efficacy in Inflammatory Bowel Disease

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Oral IL-10 Gene Delivery in a Microsphere-Based Formulation for Local Transfection and Therapeutic Efficacy in Inflammatory Bowel Disease Gene Therapy (2008) 15, 1200–1209 & 2008 Macmillan Publishers Limited All rights reserved 0969-7128/08 $30.00 www.nature.com/gt ORIGINAL ARTICLE Oral IL-10 gene delivery in a microsphere-based formulation for local transfection and therapeutic efficacy in inflammatory bowel disease MD Bhavsar and MM Amiji Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA The objective of this study was to examine the potential of IL-1a, IL-1b and IL-12, as well as certain chemokines. The oral interleukin-10 (IL-10) gene therapy for the treatment therapeutic benefits of transfected IL-10 were further of inflammatory bowel disease (IBD). Nanoparticles-in-micro- demonstrated by an increase in body weight, favorable sphere oral system (NiMOS) was formulated with murine clinical activity score, restoration in colon length and weight, IL-10-expressing plasmid DNA in type-B gelatin nanoparticles, and suppression of inflammatory response as assessed by which were further encapsulated in poly(epsilon-caprolac- tissue histological analysis and myeloperoxidase activity. tone) microsphere matrix. Upon oral administration in an The results of this study provide highly encouraging evidence acute colitis model, IL-10 expression in the large intestine of oral gene delivery and transfection and potential utility in was measured by quantitative real-time PCR and ELISA. IBD therapy. The locally expressed IL-10 was able to suppress the Gene Therapy (2008) 15, 1200–1209; doi:10.1038/gt.2008.67; levels of proinflammatory cytokines, such as IFN-g, TNF-a, published online 17 April 2008 Keywords: nanoparticles-in-microsphere oral system; non-viral vector; oral gene therapy; IL-10 transfection; inflammatory bowel disease Introduction IL-10 in suppression of inflammation in a trinitrobenze- nesulfonic acid (TNBS)-induced acute colitis animal Recent evidence supports the view that inflammatory model.6,9,10 Systemic administration of recombinant IL-10 bowel disease (IBD) is caused by genetically determined has been investigated in several small clinical trials with dysregulation of the mucosal immune response to limited success.11 Nakase et al.12 administered IL-10 luminal antigens derived from the intestinal micro- protein in gelatin microspheres to IL-10/(À/À) knockout flora.1–4 Activated T lymphocytes mediating inflamma- mice and showed some efficacy. Genetically engineered tion have been identified for the two phenotypes of IBD. Lactococcous lactis have also been developed for local Activated Th1 lymphocytes incline more toward the delivery of IL-10 protein in the intestinal lumen upon proinflammatory cytokines, which include tumor necro- oral administration.13 Local delivery of plasmid DNA sis factor-a (TNF-a), interferon-g (IFN-g), interleukin-1 encoding for IL-10 has also been reported and much of (IL-1) and IL-12. The activated lymphocytes in ulcerative the effort has been made with the use of viral vectors, colitis exhibit increased levels of IL-5, IL-6 and trans- including replication-deficient adenoviruses.6,9,10,14 forming growth factor-b (TGF-b).5 Although viral vectors have been used successfully in Interleukin-10 plays a very important role in the preclinical studies, the potential for toxicity of viruses, immunological balance of the mucosal immune system. especially upon chronic administration, is a major It acts by inhibiting the production of proinflammatory concern when it comes to translation of this experimental cytokines from activated macrophages and, thus inhibits strategy into clinical reality.15,16 We and others17–19 have, antigen presentation and effector functions. IL-10 is therefore, focused on development of safe and effective also known to inhibit chemokines, including monocyte nonviral gene delivery systems. Among several exam- inflammatory protein-1a (MIP-1a) and eotaxin, along ples of nonviral vectors, polymeric gene delivery systems with inhibition in the expression of inducible nitric oxide have received significant attention.17–23 synthase and cyclooxygenase-2 in macrophages.6–8 Sev- In previous studies, we have described the formula- eral researchers have demonstrated the usefulness of tion development, characterization, optimization and preliminary in vivo transfection of reporter plasmids Correspondence: Professor MM Amiji, Department of Pharmaceu- upon oral administration of nanoparticles-in-micro- tical Sciences, School of Pharmacy, Northeastern University, Room sphere oral system (NiMOS) formulations in animal 110 Mugar Life Sciences Building, 360 Huntington Avenue, Boston, models.24,25 NiMOS is a biodegradable and biocompa- MA 02115-5005, USA. E-mail: [email protected] tible polymer-based microparticle system capable of Received 4 December 2007; revised 13 February 2008; accepted 19 plasmid DNA delivery and local transfection upon oral February 2008; published online 17 April 2008 administration. This delivery system is specifically Oral IL-10 gene therapy for IBD MD Bhavsar and MM Amiji 1201 engineered for oral gene therapy, where the DNA- gelatin nanoparticles and in NiMOS. The plasmid DNA encapsulated gelatin nanoparticles can be released in encapsulation efficiency in gelatin nanoparticles was the intestine from poly(epsilon-caprolactone) matrix due greater than 93% at 0.5% (w/w) concentration. When to lipase-induced degradation. Once released, the nano- DNA-containing gelatin nanoparticles were further particles can be endocytosed by the cells of the intestinal encapsulated in NiMOS, the final DNA loading lumen to afford efficient transfection and transgene efficiency was found to be approximately 46% as expression. The solvent displacement technique em- determined by DNA extraction using dichloromethane ployed to formulate type B gelatin nanoparticles and protease digestion of gelatin nanoparticles to release encapsulating plasmid DNA has been previously opti- encapsulated DNA. mized and reported by our laboratory.26,27 To illustrate the utility of type B gelatin nanoparticles for systemic Local IL-10 transfection upon oral administration gene therapy, we have administered reporter and Assessment of plasmid composition and purity. The therapeutic (sFlt-1 expressing) plasmid DNA in poly pORF5-mIL-10 plasmid, purchased from InvivoGen (San (ethylene glycol)-modified nanoparticles for efficient and Diego, CA, USA) in transformed Escherichia coli, was sustained transgene expression and antiangiogenic ther- further amplified and purified from culture using the apeutic efficacy in solid tumor models.19,28–30 Plasmid Giga purification kit (Qiagen, Valencia, CA, To further evaluate the potential of NiMOS in oral USA). The plasmid composition and purity, as assessed therapeutic gene therapy, in this study, we show local by agarose gel electrophoresis, is shown in Figure 2a. transfection of IL-10 and therapeutic efficacy in TNBS- Lane 1 of the agarose gel is 2–10 kbp supercoiled ladder, induced acute colitis model developed in Balb/c mice. lane 2 is intact plasmid DNA (that is, pORF5-mIL-10), lane 3 is 1–10 kbp linear plasmid ladder, lane 4 is 100 kbp ladder and lane 5 is pORF5-mIL-10 plasmid DNA treated Results with endonucleases NcoI and NheI. The size of pORF5- IL-10-expressing plasmid DNA-encapsulated NiMOS mIL-10 is 3.7 kbp and the band seen in Figure 2a in lane 2 is between 3 and 5 kbp, suggesting that the plasmid Figure 1 shows the cross-sectional schematic of NiMOS DNA is pORF5-mIL-10. To further confirm the purity of and the scanning electron microscopy (SEM) images the isolated plasmid DNA, it was further incubated with obtained for gelatin nanoparticles. The SEM image restriction enzymes NcoI and NheI, which resulted in the confirmed the formation of small spherical type B gelatin formation of two fragment of plasmid DNA that were nanoparticles with encapsulated plasmid DNA expres- about 3.1 kbp and 570 bp. Lane 5 in Figure 2a shows two sing murine IL-10. The average particle diameter of the bands representing 3.1 kbp and the other smaller band resulting microspheres, as determined by Coulter analy- was between 500 and 600 bp, thus further confirming the sis using Multisizer 3 and by SEM, was in the range of composition of pORF5-mIL-10. 2–5 mm. Figure 1 also shows an inset of a NiMOS showing the spherical nature of NiMOS and smooth surface resulting from encapsulation of gelatin nanoparticles Local transfection assessment by quantitative within the poly(epsilon-caprolactone) matrix. PicoGreen RT-PCR. Quantitative real time (RT)-PCR analysis in dsDNA fluorescent assay was used to quantitate the the large intestine tissue was carried out to determine the capacity and efficiency of plasmid DNA encapsulation in IL-10 transgene expression at the mRNA level upon oral Plasmid DNA (i.e., pORF5- mIL-10)-Containing Microsphere matrix composed Gelatin Nanoparticles of Poly(epsilon-caprolactone) Particle Particle ~ 200 nm Cross Sectional View 2 -5 µm Size of NiMOS Size DNA DNA Loading 93-98% Loading ~ 46 % Efficiency Efficiency Figure 1 Schematic illustration showing the cross-sectional view of nanoparticles-in-microsphere oral system (NiMOS). On the left is the scanning electron microscopy (SEM) image of gelatin nanoparticles, which are less than 200 nm in diameter, and can physically encapsulate plasmid DNA at a loading efficiency of >93%. On the right is the SEM image of 2–5 mm NiMOS with the overall DNA encapsulation efficiency of B46%. Gene Therapy Oral IL-10 gene therapy for IBD MD Bhavsar and MM Amiji 1202 1 234 5 ~3.13kbp ~3.7kbp ~ 4 Kbp ~ 3 Kbp 600 bp 570 bp m IL-10 12500 m L32 10000 7500 5000 2500 mIL-10 (relative amounts) 0 Naïve Colitis Colitis Colitis No Colitis No Trtmnt Gel nps + pIL-10 NiMOS + pIL-10 200 ∗∗ 150 100 50 IL-10 (pg/mg of total protein) 0 10 Naive NiMOS + pIL-10 ** p<0.05 Colitis- No Trtmnt Gel nps + pIL- Figure 2 Murine interleukin (IL)-10 transgene expression using nanoparticles-in-microsphere oral system (NiMOS) in an acute colitis model. Qualitative agarose gel electrophoresis performed on pORF5-mIL-10 (B3.7 kbp) isolated from cultured Escherichia coli to show the purity and composition of the plasmid (a).
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