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    Drug Delivery

    Bioactivities and Release Profiles of Atorvastatin using Keratin-based Hydrogels

    (L-465) Bioactivities and Release Profiles of Atorvastatin using Keratin-based Hydrogels

    Saturday, October 14, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row L - Poster # 465
    Introduction::

    Introduction:  Statins are commonly prescribed medications used to decrease cholesterol by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, but importantly linked to have pleiotropic anti-fibrotic effects, possibly through the transforming growth factor beta (TGFB) signaling pathway which either prevents the activation of quiescent fibroblast or transdifferentiation of progenitors into myofibroblast, the cell implicated for the harmful fibrous encapsulation response.  In this study, the bioactivities of statin, as atorvastatin (Ator), were investigated when delivered using keratin-based (KTN) hydrogels that are currently being explored for fibrosis mitigation in cardiovascular implantable electronic devices.



    Materials and Methods:: Materials and Methods:  The Ator’s (Atorvastatin Calcium, Dr. Reddy’s) dose effect to fibroblasts precursor were evaluated using mesenchymal stem cells’ (MSCs, ASC52telo, ATCC) viability via an MTT assay.  This in vitro dose-response test was also employed using fibroblast and myofibroblast cell models.  KTN drug-carrier gels were obtained from the residual and insoluble fraction of the thioglycolic acid hair reduction process.  To increase Ator’s gel retention, additional positively-charged Ca ions were mixed to electrostatically-conjugate the negatively-charged KTN and Ator.  After absorption, Ator release was performed at 0, 0.25, 0.5, 1, 2, 4, and 8 h in PBS.  Calcium alginate (CaALG) gels spheres were used as a control drug vehicle biomaterial.  The released Ator was again tested for its bioactivities.

    Results, Conclusions, and Discussions:: Results and Discussion:  Low atorvastatin doses did not affect the viability of MSCs, which enabled them to naturally proliferate and increase in number (Fig. 1, green line); but at relatively high increasing doses led to responsive inhibition (red line), with an IC50 of ~114 μg/mL (at similar range with fibro- and myofibroblasts, but with even higher IC50 using non-fibroblastic suggesting cell-specific actions).  KTN gels (Fig. 2, left) without or with Ca ions (KTN+Ca) absorbed Ator at ≥ 1.3 μg/mg, then was subsequently released at ~7% and 3% at the 8-h time point (Fig. 2, right), respectively.  This > 2-fold reduction of Ator release in KTN+Ca vs. KTN, proved that additional Ca acted as a multivalent positive bridge to hold the negatively-charged KTN matrix and Ator drug within the hydrogel.  CaALG, containing abundant Ca, exhibited an even slower release profile.  The gel-released Ator was found to preserve its bioactivities in inhibiting fibroblast-type cells.  We are currently verifying our preliminary findings and probing for potential TGFB molecular mechanisms of action.

    Conclusion:  Atorvastatin displays properties of inhibiting fibroblast proliferation as its concentration increases.  KTN hydrogels show capable sequestration and slow in vitro delivery of functional atorvastatin.  A follow-up in vivo mouse subcutaneous implantation study will be further explored to observe statin’s fibrous encapsulation and inflammation responses out of keratin-based hydrogels.


    Acknowledgements (Optional): : Acknowledgements:  Fusion Beauty Salon, Stylush Salon and Laser, Fresh Cuts, and Hair Designers for sources of human hair samples.

    References (Optional): :