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. 2020 Oct;15(25):2459-2474.
doi: 10.2217/nnm-2020-0280. Epub 2020 Sep 25.

Colonic delivery of vasoactive intestinal peptide nanomedicine alleviates colitis and shows promise as an oral capsule

Dulari Jayawardena  1   2 , Arivarasu N Anbazhagan  1 , Shubha Priyamvada  1 , Anoop Kumar  1   3 , Seema Saksena  1   3 , Hayat Onyuksel  2 , Pradeep K Dudeja  1   2   3
Affiliations

Colonic delivery of vasoactive intestinal peptide nanomedicine alleviates colitis and shows promise as an oral capsule

Dulari Jayawardena et al. Nanomedicine (Lond). 2020 Oct.

Abstract

Aim: To evaluate the efficacy of locally delivered nanomedicine, vasoactive intestinal peptide in sterically stabilized micelles (VIP-SSM) to the colon and conduct in vitro release studies of a potential oral formulation. Materials & methods: Intracolonic instillation of VIP-SSM was tested in a mouse model of dextran sulfate sodium-induced colitis. Based on the effective mouse dose, human equivalent dose containing nanomedicine powder was filled into enteric coated capsules for in vitro release testing. Results: Colonic delivery of VIP-SSM significantly alleviated colitis. VIP-SSM containing capsules completely dissolved at colonic pH allowing micelles to reform with active VIP. Capsule formulations exhibited reproducible release profiles when stored up to 6 weeks demonstrating stability. Conclusion: VIP-SSM is an effective nanomedicine formulation which appears to have potential for oral treatment of colitis in humans. [Formula: see text].

Keywords: VIP nanomedicine; colitis; colonic delivery; inflammatory bowel disease; oral capsule form; oral nanomedicine; slc26a3; sterically stabilized micelles; targeted delivery.

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Conflict of interest statement

Financial & competing interests disclosure

These studies were supported by the NIDDK grants R01 DK54016, R01 DK92441 (PK Dudeja) and the Department of Veterans Affairs BX 002011 (PK Dudeja) and VA SRCS Award (IK6 BX005242, PK Dudeja), BX 002867 (S Saksena), BX004719 (A Kumar), UIC Dean’s Fellowship (D Jayawardena) and TUBITAK Award (H Onyuksel). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR15482 from the National Center for Research Resources, NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. Intra-rectal administration of a single dose of vasoactive intestinal peptide in sterically stabilized micelles to the colonic lumen improved bodyweight and colonic length of mice after dextran sulfate sodium insult.
(A) Schematic representation of animal study design for local nanomedicine administration in DSS colitis. (B) Bodyweight change in all treatment groups through the course of the study. (C) Representative photograph of whole excised colons of mice in all groups and graphical representation of average length per group. Data represented as mean ± SEM, n = 6. **p < 0.005; ***p < 0.0005; ****p < 0.0001 versus control, #p < 0.05; ##p < 0.005 versus DSS; ap < 0.05 DSS-VIP-SSM versus DSS-VIP. DSS: Dextran sulfate sodium; VIP: Vasoactive intestinal peptide; VIP-SSM: Vasoactive intestinal peptide in sterically stabilized micelles.
Figure 2.
Figure 2.. Locally administered vasoactive intestinal peptide in sterically stabilized micelles nanomedicine significantly reduced mRNA expression of pro-inflammatory cytokines in the distal colonic mucosa.
mRNA isolated from mouse distal colonic mucosa was subjected to qPCR with specific primers for (A) IL-1β, (B) CXCL-1 and (C) CXCL-2. Gene expression was normalized to internal control GAPDH. Data represented as mean ± SEM, n = 6. *p < 0.05; **p < 0.005 versus control; #p < 0.05; ##p < 0.005 versus DSS. CXCL-1: C-X-C motif chemokine ligand-1; CXCL-2: C-X-C motif chemokine ligand-2; DSS: Dextran sulfate sodium; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase.
Figure 3.
Figure 3.. Locally delivered vasoactive intestinal peptide in sterically stabilized micelles alleviates colonic inflammation and myeloperoxidase activity in dextran sulfate sodium mice.
(A) Representative colonic micrographs of all treatment groups after hematoxylin and eosin stain. (B) Graphical representation of histopathological score of average in each group. (C) Bar diagram depicting MPO activity in distal colonic tissues in all treatment groups. Data represented as mean ± SEM, n = 6. **p < 0.005; ***p < 0.0005; ****p < 0.0001 versus control; ##p < 0.005; ####p < 0.0001 versus DSS, ap < 0.0001 DSS-VIP-SSM versus DSS-VIP. DSS: Dextran sulfate sodium; MPO: Myeloperoxidase; VIP-SSM: Vasoactive intestinal peptide in sterically stabilized micelles.
Figure 4.
Figure 4.. Colonic delivery of vasoactive intestinal peptide in sterically stabilized micelles nanomedicine rescued mice from dextran sulfate sodium induced goblet cell loss.
(A) Representative micrographs and (B) graphical representation of distal colonic tissues stained with PAS stain showing goblet cells (indicated with arrow heads). Data represented as mean ± SEM, n = 6. **p < 0.005; ****p < 0.0001 versus control; ####p < 0.0001 versus DSS, ap < 0.05 DSS-VIP-SSM versus DSS-VIP. DSS: Dextran sulfate sodium; PAS: Periodic acid Schiff; VIP-SSM: Vasoactive intestinal peptide in sterically stabilized micelles.
Figure 5.
Figure 5.. Vasoactive intestinal peptide in sterically stabilized micelles intrarectal delivery attenuated dextran sulfate sodium-induced DRA loss in mice distal colon.
(A) Representative micrographs of fluorescently stained DRA (red) with the apical marker villin (green) and DAPI (blue). (B) Graphical representation of quantified DRA immunofluorescence intensity (arbitrary units) across treatment groups. Data represented as average ± SEM, n = 3 with 10 data points per n. **p < 0.005; ***p < 0.0005 versus control; ###p < 0.0005 versus DSS, ap < 0.005 DSS-VIP-SSM versus DSS-VIP. DAPI: 4,6-diamino-2-phenylindole; DSS: Dextran sulfate sodium; VIP-SSM: Vasoactive intestinal peptide in sterically stabilized micelles.
Figure 6.
Figure 6.. Dextran sulfate sodium model of colitis has negligible effects on VPAC1 expression in the distal colon.
(A) Graphical representation of VPAC1 mRNA in the Distal colon. Gene expression normalized to internal control GAPDH. mRNA isolated from mouse distal colon was subjected to qPCR with specific primers for VPAC1. Data represented as average ± SEM, n = 6. (B) Immunofluorescence staining of VPAC1 (red) and DAPI (blue) in distal colonic tissue sections. DAPI: 4,6-diamino-2-phenylindole; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; qPCR: Quantitative polymerase chain reaction.
Figure 7.
Figure 7.. Freeze-dried vasoactive intestinal peptide in sterically stabilized micelles nanomedicine containing capsules completely dissolve in buffer (pH 6) releasing nanomedicine with active vasoactive intestinal peptide.
(A) Representative photographs of the capsule filling process for freeze dried VIP-SSM at human equivalent dose. (B) Complete dissolution of VIP-SSM capsules at 40 min in 37°C while continuous stirring. Red arrow points at the capsule. (C) Particle size distribution of dissolution solution at given time points (from 20 min onward where detectable amounts of nanomedicine was released to solution). (D) Percentage release of full-length VIP from capsules as determined by VIP EIA. EIA: Enzyme immuno assay; VIP-SSM: Vasoactive intestinal peptide in sterically stabilized micelles.
Figure 8.
Figure 8.. Stability of freeze-dried vasoactive intestinal peptide in sterically stabilized micelles nanomedicine capsules.
(A) Comparison of percentage of full-length VIP released from capsules containing VIP-SSM nanomedicine (blue) and VIP released from capsules filled with a commercially used diluent filler: lactose (purple). (B) Release profiles of VIP-SSM capsules stored in airtight glass containers at 4°C up to 6 weeks. VIP EIA was used to determine release of full-length VIP peptide. Data points are the average of at least three independent experiments ± SEM. EIA: Enzyme immuno assay; VIP-SSM: Vasoactive intestinal peptide in sterically stabilized micelles.
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