Transdermal delivery of metformin using microneedle and iontophoresis for combating obesity

dc.contributor.committeeChairGalyean, Shannon
dc.contributor.committeeMemberWang, Shu
dc.contributor.committeeMemberMoustaid-Moussa, Naima
dc.contributor.committeeMemberSingh Gill, Harvinder
dc.contributor.committeeMemberZhao, Ling
dc.creatorAbbasi, Mehrnaz
dc.creator.orcid0000-0003-4287-2133
dc.date.accessioned2021-01-25T20:26:16Z
dc.date.available2021-01-25T20:26:16Z
dc.date.created2020-12
dc.date.issued2020-12
dc.date.submittedDecember 2020
dc.date.updated2021-01-25T20:26:17Z
dc.description.abstractThe prevalence of obesity and overweight is dramatically increasing, making them a global concern. It increases the risk of many diseases particularly diabetes, hypertension, osteoarthritis, and heart disease. Combating obesity, however, is complicated due to the extreme fact that current obesity treatments such as lifestyle intervention, pharmacotherapy and surgeries are associated with low effectiveness or undesired side effects. Therefore, an effective alternative therapeutic approach is critically needed. In contrast to white adipose tissue (WAT), brown adipose tissue (BAT) and beige adipose tissue known as thermogenic organs, participate in energy expenditure. WAT browning (conversion of white adipocytes to beige cells) represents an important strategy for obesity treatment. Direct drug delivery to WAT to promote its browning is highly desired. Metformin is the most commonly used FDA approved antidiabetic drug, which has been prescribed widely. In addition to lowering blood glucose levels, emerging evidence suggest that metformin can induce browning of WAT through phosphorylation and activation of AMP-activated protein kinase (AMPK). However, oral administration of metformin results in a low level of oral bioavailability, a high level of gastrointestinal side effects, and fast renal clearance, these lower its browning efficacy. Because of poor patient compliance and subsequent infection at the injection site, subcutaneous injection directly into the WAT using a standard hypodermic needle is also not desired. Thus, localized delivery of metformin directly to SubQ WAT using transdermal delivery approach is an attractive alternative. Our overall hypothesis was that delivery of metformin to SubQ WAT using transdermal microneedle (MN) in combination with iontophoresis (MN + Iontophoresis) provides higher obesity therapeutic effectiveness than oral administration and SubQ WAT injection by browning of WAT. Delivery effectiveness was initially determined using MN derma rollers and iontophoresis in vitro, by applying 2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- (lissamine rhodamine B sulfonyl (Rhod-PE) dye on the pig skin. The results indicated that MN + Iontophoresis increased dye delivery to the SubQ WAT. We further developed 1,1′-dioctadecyl-3,3,3′,3′- tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (DID)/Rhod-PE dye or metformin-loaded biodegradable MN patches using a mold-casting method. Then, we determined the application and delivery effectiveness of developed MN + Iontophoresis for SubQ WAT delivery by using pig skin (in vitro), and visualizing biodistribution of delivered DID dye upon applying MN + Iontophoresis on the skin above inguinal WAT (IgWAT) depots of C57BL/6J mice (in vivo). At last, we determined the anti-obesity effects of metformin-loaded MN + Iontophoresis as compared with oral gavage and SubQ WAT injection in C57BL/6J obese mice. After feeding a high fat diet (HFD) for 4 weeks, mice received one of the following treatment: 1. MN + Iontophoresis (Metformin), 2. MN + Iontophoresis (Blank), 3. MN alone, 4. Iontophoresis alone, 5. IgWAT injection (Metformin), 6. IgWAT injection (Saline), 7. Gavage (Metformin) and 8. Gavage (Saline) for additional 5 weeks. Metformin dose was 3 mg/kg body weight/day. Mice in the MN + Iontophoresis (metformin) treatment group had the lowest body weight and fat mass, and the highest respiratory exchange ratio (RER), which were correlated with the lowest IgWAT weight, the smallest adipocytes size, the highest metformin content in IgWAT, the highest uncoupling protein 1 (UCP1) mRNA and protein expression levels in IgWAT, the highest protein expression levels of phosphorylated AMPK (pAMPK) in IgWAT, while no significant differences were found in food intake among all treatment groups. In summary, we have successfully developed dissolving metformin-loaded MN + Iontophoresis for combating obesity via browning of WAT. The delivery effectiveness of this approach was examined both in vitro and in vivo which was confirmed by major deposition of delivered medication into the target SubQ WAT. It is demonstrated that transdermal MN + Iontophoresis approach can enhance anti-obesity benefits of metformin and improved energy metabolism through browning of WAT as compared to conventional SubQ WAT injection and oral administration in HFD-induced C57BL/6J obese mice. Such MN + Iontophoresis approach can achieve a much lower effective dose as compared to traditional delivery approaches and enables easy, self-administered long-term treatment. The results from current study provides promising insights toward treatment of obesity and its related metabolic conditions in a much more comfortable, easy and safe regimen.
dc.description.abstractEmbargo status: Restricted until January 2026. To request access, click on the PDF link to the left.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/2346/86751
dc.language.isoeng
dc.rights.availabilityRestricted until January 2026.
dc.subjectObesity
dc.subjectMetformin
dc.subjectTansdermal
dc.subjectMicroneedle
dc.subjectBrowning
dc.subjectTargeted delivery
dc.subjectSubcutaneous adipose tissue
dc.subjectC57BL/6J mice
dc.titleTransdermal delivery of metformin using microneedle and iontophoresis for combating obesity
dc.typeThesis
dc.type.materialtext
local.embargo.lift2025-12-01
local.embargo.terms2025-12-01
thesis.degree.departmentNutritional Sciences
thesis.degree.disciplineNutritional Sciences
thesis.degree.grantorTexas Tech University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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