Formulation and In Vitro-In Vivo Evaluation of Black Raspberry Extract-Loaded PLGA/PLA Injectable Millicylindrical Implants for Sustained Delivery of Chemopreventive Anthocyanins

Abstract

Purpose-The objective of this study was to formulate and evaluate freeze-dried black raspberry (FBR) ethanol extract (RE) loaded poly(DL-lactic-co-glycolic acid) (PLGA) and poly(DL-lactic acid) (PLA) injectable millicylindrical implants for sustained delivery of chemopreventive FBR anthocyanins (cyanidin-3-sambubioside (CS), cyanidin-3-glucoside (CG) and cyanidin-3-rutinoside (CR)).Methods-Identification and quantitation of CS, CG, and CR in RE was performed by mass spectroscopy and HPLC. RE:triacetyl-β-cyclodextrin (TA-β-CD) inclusion complex (IC) was prepared by a kneading method and characterized by X-ray diffraction (XRD), nuclear magnetic resonance spectroscopy (NMR) and UV-visible spectroscopy. RE or RE:TA-β-CD IC-loaded PLGA or PLA implants were prepared by a solvent extrusion method. In vitro and in vivo controlled release studies were conducted in phosphate-buffered saline Tween-80 (pH 7.4, 37°C) and after subcutaneous administration in male Sprague-Dawley rats, respectively. Anthocyanins were quantified by HPLC at 520 nm.Results-The content of CS, CG, and CR in RE was 0.2, 1.5, and 3.5 wt%, respectively. The chemical stability of anthocyanins in solution was determined to be pH-dependent, and their degradation rate increased with an increase in pH from 2.4 to 7.4. PLGA/PLA millicylindrical implants loaded with 5 or 10 wt% RE exhibited a high initial burst and short release duration of anthocyanins (35-52 and 80-100% CG + CR release after 1 and 14 days, respectively). The cause for rapid anthocyanins release was linked to higher polymer water uptake and porosity associated with the high osmolytic components of large non-anthocyanin fraction of RE. XRD, 1 H NMR and UV-visible spectroscopy indicated that the non-anthocyanin fraction molecules of RE formed an IC with TA-β-CD, decreasing the hydrophilicity of RE. Formation of an IC with hydrophobic carrier, TA-β-CD, provided better in vitro/in vivo sustained release of FBR anthocyanins (16-24 and 97-99% CG + CR release, respectively, after 1 and 28 days from 20 wt% RE:TA-β-CD IC/PLA implants) over 1 month, owing to reduced polymer water uptake and porosity.4 To whom correspondence should be addressed. (schwende@umich.edu). Conclusion-PLA injectable millicylindrical implants loaded with RE:TA-β-CD IC are optimal dosage forms for 1-month slow and continuous delivery of chemopreventive FBR anthocyanins. NIH Public Access

Exosomal formulation of anthocyanidins against multiple cancer types

“…Although the treatment resulted in histopathologic regression of lesions, the chemopreventive benefit was not observed in all trial participants [36]. In another attempt, these groups formulated millicylindrical injectable implants of FBR ethanol extract using poly (DL-lactic-co-glycolic acid) (PLGA) and poly (DL-lactic acid) (PLA) for sustained delivery of chemopreventive FBR anthocyanins [37,57]. Although implantable vehicles alleviate concerns with multiple dosing schedules associated with gel formulations, this is not patient friendly.…”

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

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Poly(Lactic-Co-Glycolic Acid) Based Drug Delivery Devices For Tissue Engineering And Regenerative Medicine

“…Among the different forms of PLGA-based DDSs, microspheres or microparticles are the most common. Other types include nanoparticles (68) , films (45) , cylinders (22) , in situ forming implants or microparticles (23) , scaffolds (82) , and foams (57) . PLGA implants may be surgically inserted at the desired location, giving the advantage of local drug delivery of, for example, antibiotics or anti-cancer drugs (80,83) .…”