TY - JOUR
T1 - Poly(lactic-co-glycolic Acid) Nanoparticle Encapsulated 17β-Estradiol Improves Spatial Memory and Increases Uterine Stimulation in Middle-Aged Ovariectomized Rats
AU - Prakapenka, Alesia V.
AU - Quihuis, Alicia M.
AU - Carson, Catherine G.
AU - Patel, Shruti
AU - Bimonte-Nelson, Heather A.
AU - Sirianni, Rachael W.
N1 - Funding Information:
Content of this manuscript was previously published as part of AP’s dissertation thesis (Prakapenka, 2018). The authors would like to acknowledge the National Institutes of Health, National Science Foundation, Barrow Neurological Institute (BNI), Arizona State University (ASU)-BNI Interdepartmental Neuroscience Program, ASU Department of Psychology, and the ARCS Foundation for their support. We also thank Dr. Laurence Demers and the Core Endocrinology Laboratory of the Pennsylvania State University, College of Medicine for performing the hormone assays.
Funding Information:
Content of this manuscript was previously published as part of AP's dissertation thesis (Prakapenka, 2018). The authors would like to acknowledge the National Institutes of Health, National Science Foundation, Barrow Neurological Institute (BNI), Arizona State University (ASU)-BNI Interdepartmental Neuroscience Program, ASU Department of Psychology, and the ARCS Foundation for their support. We also thank Dr. Laurence Demers and the Core Endocrinology Laboratory of the Pennsylvania State University, College of Medicine for performing the hormone assays. Funding. AP was funded by the National Science Foundation Graduate Research Fellowship (DGE-1311230). HB-N was funded by the National Institute on Aging (AG028084), state of Arizona, Arizona Department of Health Services (ADHS14-052688), National Institutes of Health (NIH) Alzheimer's Disease Core Center (P30AG019610), Arizona State University Office of Knowledge Enterprise Development, College of Liberal Arts and Sciences, and Department of Psychology. RS was funded by the Barrow Neurological Institute and the University of Texas Health Science Center at Houston.
Funding Information:
AP was funded by the National Science Foundation Graduate Research Fellowship (DGE-1311230). HB-N was funded by the National Institute on Aging (AG028084), state of Arizona, Arizona Department of Health Services (ADHS14-052688), National Institutes of Health (NIH) Alzheimer’s Disease Core Center (P30AG019610), Arizona State University Office of Knowledge Enterprise Development, College of Liberal Arts and Sciences, and Department of Psychology. RS was funded by the Barrow Neurological Institute and the University of Texas Health Science Center at Houston.
Publisher Copyright:
© Copyright © 2020 Prakapenka, Quihuis, Carson, Patel, Bimonte-Nelson and Sirianni.
PY - 2020/12/16
Y1 - 2020/12/16
N2 - Hormone therapy that contains 17β-estradiol (E2) is used commonly for treatment of symptoms associated with menopause. E2 treatment has been shown to improve cognitive function following the decrease in ovarian hormones that is characteristic of menopause. However, once in circulation, the majority of E2 is bound to serum hormone binding globulin or albumin, becoming biologically inactive. Thus, therapeutic efficacy of E2 stands to benefit from increased bioavailability via sustained release of the hormone. Here, we focus on the encapsulation of E2 within polymeric nanoparticles composed of poly(lactic-co-glycolic) acid (PLGA). PLGA agent encapsulation offers several delivery advantages, including improved bioavailability and sustained biological activity of encapsulated agents. We hypothesized that delivery of E2 from PLGA nanoparticles would enhance the beneficial cognitive effects of E2 relative to free E2 or non-hormone loaded nanoparticle controls in a rat model of menopause. To test this hypothesis, spatial learning and memory were assessed in middle-aged ovariectomized rats receiving weekly subcutaneous treatment of either oil-control, free (oil-solubilized) E2, blank (non-hormone loaded) PLGA, or E2-loaded PLGA. Unexpectedly, learning and memory differed significantly between the two vehicle control groups. E2-loaded PLGA nanoparticles improved learning and memory relative to its control, while learning and memory were not different between free E2 and its vehicle control. These results suggest that delivery of E2 from PLGA nanoparticles offered cognitive benefit. However, when evaluating peripheral burden, E2-loaded PLGA was found to increase uterine stimulation compared to free E2, which is an undesired outcome, as estrogen exposure increases uterine cancer risk. In sum, a weekly E2 treatment regimen of E2 from PLGA nanoparticles increased cognitive efficacy and was accompanied with an adverse impact on the periphery, effects that may be due to the improved agent bioavailability and sustained biological activity offered by PLGA nanoparticle encapsulation. These findings underscore the risk of non-specific enhancement of E2 delivery and provide a basic framework for the study and development of E2's efficacy as a cognitive therapeutic with the aid of customizable polymeric nano-carriers.
AB - Hormone therapy that contains 17β-estradiol (E2) is used commonly for treatment of symptoms associated with menopause. E2 treatment has been shown to improve cognitive function following the decrease in ovarian hormones that is characteristic of menopause. However, once in circulation, the majority of E2 is bound to serum hormone binding globulin or albumin, becoming biologically inactive. Thus, therapeutic efficacy of E2 stands to benefit from increased bioavailability via sustained release of the hormone. Here, we focus on the encapsulation of E2 within polymeric nanoparticles composed of poly(lactic-co-glycolic) acid (PLGA). PLGA agent encapsulation offers several delivery advantages, including improved bioavailability and sustained biological activity of encapsulated agents. We hypothesized that delivery of E2 from PLGA nanoparticles would enhance the beneficial cognitive effects of E2 relative to free E2 or non-hormone loaded nanoparticle controls in a rat model of menopause. To test this hypothesis, spatial learning and memory were assessed in middle-aged ovariectomized rats receiving weekly subcutaneous treatment of either oil-control, free (oil-solubilized) E2, blank (non-hormone loaded) PLGA, or E2-loaded PLGA. Unexpectedly, learning and memory differed significantly between the two vehicle control groups. E2-loaded PLGA nanoparticles improved learning and memory relative to its control, while learning and memory were not different between free E2 and its vehicle control. These results suggest that delivery of E2 from PLGA nanoparticles offered cognitive benefit. However, when evaluating peripheral burden, E2-loaded PLGA was found to increase uterine stimulation compared to free E2, which is an undesired outcome, as estrogen exposure increases uterine cancer risk. In sum, a weekly E2 treatment regimen of E2 from PLGA nanoparticles increased cognitive efficacy and was accompanied with an adverse impact on the periphery, effects that may be due to the improved agent bioavailability and sustained biological activity offered by PLGA nanoparticle encapsulation. These findings underscore the risk of non-specific enhancement of E2 delivery and provide a basic framework for the study and development of E2's efficacy as a cognitive therapeutic with the aid of customizable polymeric nano-carriers.
KW - PLGA
KW - delivery
KW - estrogen
KW - learning
KW - memory
KW - menopause
UR - http://www.scopus.com/inward/record.url?scp=85098500370&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098500370&partnerID=8YFLogxK
U2 - 10.3389/fnbeh.2020.597690
DO - 10.3389/fnbeh.2020.597690
M3 - Article
AN - SCOPUS:85098500370
SN - 1662-5153
VL - 14
JO - Frontiers in Behavioral Neuroscience
JF - Frontiers in Behavioral Neuroscience
M1 - 597690
ER -