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17beta-estradiol loaded poly(lactic-co-glycolic acid) nanoparticles for cognitive therapy

Alesia Prakapenka1, 2, 3, 4, Alicia M. Quihuis1, 3, Ryoko Hiroi1, 3, Catherine G. Carson1, 3, Shruti Patel1, 3, Eugene Chung2, 4, Danielle M. Diperna4, Heather A. Bimonte-Nelson1, 3 and Rachael W. Sirianni4, 5
  • 1 Arizona State University, Department of Psychology, United States
  • 2 Arizona State University, School of Life Sciences, United States
  • 3 Arizona Alzheimer's Consortium, United States
  • 4 Barrow Neurological Institute, Barrow Brain Tumor Research Center, United States
  • 5 Arizona State University, Department of Biomedical Engineering, United States

As the average life expectancy for women continues to rise, there is an increased need to address the symptomatic consequences of decreased ovarian hormone secretion accompanying menopause. Hormone therapy can diminish undesired symptoms, including cognitive changes. 17β-estradiol (E2) is the most potent endogenous estrogen, and it is commonly used in hormone therapy. In humans and rats, E2 has been shown to enhance cognitive performance following ovarian hormone loss. E2 treatment is associated with an increased risk for endometrial cancer unless given with a progestogen. However, progestogens have undesired actions in many tissues. Thus, a treatment providing the benefits of estrogens with no progestogen would be beneficial. Because E2 is rapidly metabolized and cleared following administration, we were motivated to encapsulate E2 in nanoparticles (NPs) for controlled release. We hypothesized that sustained brain exposure to E2 via delivery from poly(lactic-co-glycolic acid) NPs would enhance cognition in ovariectomized middle-aged rats relative to free E2. First, biodistribution studies evaluated three routes of administration (intravenous, intranasal, and subcutaneous (SQ)) for payload delivery with control versus brain-targeted formulations (surface modified with rabies virus glycoprotein). Ultimately, surface modification did not justify selection of a targeted formulation, and SQ delivery provided the greatest total brain exposure to encapsulated small molecules over time. Next, we studied the effect of free E2 treatment frequency (daily, weekly, biweekly) on cognition with daily E2 administration enhancing spatial working memory performance in ovariectomized middle-aged rats. Results led us to test treatment of a sustained release formulation where rats received a weekly SQ injection of free E2 or NP-encapsulated E2 compared to vehicle controls. Behavioral measures included the water radial arm maze to assess spatial working and reference memory, and Morris maze to assess spatial reference memory. Evaluations of peripheral E2 exposure (vaginal smears, uterine horn weights), serum estrogen levels, and protein expression (NGF, BDNF) and activation (ERK, pERK) in five brain regions were performed. Rats that received NP-encapsulated E2 performed better on working memory relative to NP controls. These rats tended to have higher peripheral E2 exposure, suggesting that brain targeting will be needed to reduce peripheral exposure. Interestingly, we also observed enhanced cognition with the NP as a vehicle, an effect that has not been previously reported, possibly due to mild inflammatory responses to weekly NP injection. In sum, these data indicate that NP E2 enhances cognition relative to NP control, and that cognitive benefits are seen from NP as the vehicle. These results strengthen our understanding of hormone delivery in the context of cognitive decline, and raise interesting avenues for investigation of NP delivery in neuroimmunology.

Keywords: in vivo, Drug delivery, nanoparticle, polymer

Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.

Presentation Type: Poster

Topic: Biomaterials for therapeutic delivery

Citation: Prakapenka A, Quihuis AM, Hiroi R, Carson CG, Patel S, Chung E, Diperna DM, Bimonte-Nelson HA and Sirianni RW (2016). 17beta-estradiol loaded poly(lactic-co-glycolic acid) nanoparticles for cognitive therapy. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.01174

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Received: 27 Mar 2016; Published Online: 30 Mar 2016.