Sustained In Vitro and In Vivo Delivery of Metformin from Plant Pollen-Derived Composite Microcapsules

Abstract

We developed a dual microencapsulation platform for the type 2 diabetes drug metformin (MTF), which is aimed to increase its bioavailability. We report the use of Lycopodium clavatum sporopollenin (LCS), derived from their natural spores, and raw Phoenix dactylifera L. (date palm) pollens (DPP) for MTF microencapsulation. MTF was loaded into LCS and DPP via a vacuum and a novel method of hydration-induced swelling. The loading capacity (LC) and encapsulation efficiency (EE) percentages for MTF-loaded LCS and MTF-loaded DPP microcapsules were 14.9% ± 0.7, 29.8 ± 0.8, and 15.2% ± 0.7, 30.3 ± 1.0, respectively. The release of MTF from MTF-loaded LCS microcapsules was additionally controlled by re-encapsulating the loaded microcapsules into calcium alginate (ALG) microbeads via ionotropic gelation, where the release of MTF was found to be significantly slower and pH-dependent. The pharmacokinetic parameters, obtained from the in vivo study, revealed that the relative bioavailability of the MTF-loaded LCS-ALG beads was 1.215 times higher compared to pure MTF, following oral administration of a single dose equivalent to 25 mg/kg body weight MTF to streptozotocin (STZ)-induced diabetic male Sprague-Dawley rats. Significant hypoglycemic effect was obtained for STZ-induced diabetic rats orally treated with MTF-loaded LCS-ALG beads compared to control diabetic rats. Over a period of 29 days, the STZ-induced diabetic rats treated with MTF-loaded LCS-ALG beads showed a decrease in the aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides, cholesterol, and low-density lipoprotein-cholesterol (LDL-C) levels, as well as an increase in glutathione peroxidase (GPx) and a recovery in the oxidative stress biomarker, lipid peroxidation (LPx). In addition, histopathological studies of liver, pancreas, kidney, and testes suggested that MTF-loaded LCS-ALG beads improved the degenerative changes in organs of diabetic rats. The LCS-ALG platform for dual encapsulation of MTF achieved sustained MTF delivery and enhancement of bioavailability, as well as the improved biochemical and histopathological characteristics in in vivo studies, opening many other intriguing applications in sustained drug delivery.

Extraordinary microcarriers derived from spores and pollens

“…12 The sporopollenin exine shells can serve as an excellent substrate for several types of microcarriers due to their inherent size uniformity, 4,8,13 porosity, 14,15 elasticity, [16][17][18] amphiphilicity, 19 chemical stability, [20][21][22] anti-ultraviolet and anti-oxidation, [23][24][25] photothermal effects, 26 adhesion, [27][28][29] biocompatibility, 30 and stability within body fluids. 31 For example, their inside cavity and surface pores facilitate drug loading and cargo delivery; [30][31][32][33][34] the robust exine structure can achieve long-term preservation; 25 the unique surface decoration increases the specific surface area enhancing the adsorption of probe molecules and target detection; 35 sporopollenin is rich in carboxyl and hydroxyl groups, which can be easily functionalized or formed into composites and further derived into microrobots, 8,36 cell scaffolds, 37,38 etc. Compared to artificial microcarriers, which are complex, expensive and poorly monodispersed in mass production, the intrinsic superiorities and tailorable properties of spores and pollens make them suitable template-free materials to construct biological microcarriers or synthetic biomimetic particles.…”

Sporopollenin Microcapsule: Sunscreen Delivery System with Photoprotective Properties

“…Due to their robustness, sporopollenin microcapsules (SPMs) have been proposed for various applications, including drug delivery [ 8 , 14 , 15 ]. SPMs with different sizes and morphology can be obtained from a variety of plants, but even though many recent studies have demonstrated the capability of SPMs to control and enhance the delivery of drugs [ 16 , 17 , 18 ], only a few of them concern cutaneous and cosmetical applications [ 19 , 20 ].…”

Biochemical and histopathological evaluation of the effect of metformin and metformin nanoparticles against alloxan-induced diabetes in Rats

“…(Zhang et al,2019). A case of serious hepatotoxicity is possibly caused by metformin use at a dose of 500 mg/day for three weeks (Nathan,2008;Meligi et al, 2021). In diabetic rats treated with metformin, the pancreas showed that islets of Langerhans have a more-or less-normal cell population with the absence of degenerative changes, and blood sinusoids also appeared to be normal (Meligi et al, 2021).…”

“…A case of serious hepatotoxicity is possibly caused by metformin use at a dose of 500 mg/day for three weeks (Nathan,2008;Meligi et al, 2021). In diabetic rats treated with metformin, the pancreas showed that islets of Langerhans have a more-or less-normal cell population with the absence of degenerative changes, and blood sinusoids also appeared to be normal (Meligi et al, 2021). Drug nanoencapsulation arises to be an effective alternative to lessen the side effects of drug administration while achieving controlled release and site-specific delivery (Kumar et al, 2016).…”