(331f) Neonatal Pharmacokinetics and Biodistribution of Polymeric Nanoparticles

Presenting Author: Nuo Xu, University of Washington, US

Co-Authors: Megan Wong, Elizabeth Nance

Introduction: Therapeutic development for pediatric use has advanced in the last few decades, yet the off-label use of adult medications in pediatrics remains a significant clinical problem. The development of therapeutics for pediatrics is challenged by the lack of pharmacokinetic (PK) data in the pediatric population, a gap in data even more significant for neonates. Additionally, the role of nanomedicine, which can improve PK profiles of many therapeutics, has prominently focused on applications in adults. The US and European based pediatric formulation initiatives to investigate nanomedicine formulations for pediatric use necessitates greater understanding and greater data availability of nanomedicines in the pediatric population. In this study, we quantify the PK profiles and biodistribution of polymeric nanoparticles in neonatal rats. We focus on poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles, which play an important role in drug delivery and have been widely studied in adults. Our results provide a guide for nanotherapeutic use in neonates.

Methods: PLGA-PEG (45k:5k, LA:GA=50:50) nanoparticles were formulated using standard nanoprecipitation methods in either polysorbate 80 (P80) or Pluronic® F127 (F127) (1). The fluorescent dye CF647® was conjugated to the PLGA backbone prior to formulation. PLGA-PEG particles were characterized using dynamic light scattering, and then intraperitoneally injected into postnatal (P) day 10 Sprague Dawley rats, with n = 4 (2 males, 2 females) pups per time point. P10 rats are term equivalent to a human. Rats were sacrificed at 30 min, 1 h, 4 h, 8 h, 24 h and 72 h after administration. Organ-level and tissue-level biodistribution were characterized via UV-Vis spectrometry and confocal microscopy, respectively. PK profiles of PLGA-PEG nanoparticles in serum, brain, heart, lung, liver, spleen and kidney were calculated from a calibration curve for each tissue on UV-Vis. Tissue from pups not injected with particles served as controls.

Results: We have previously shown PLGA-PEG nanoparticles made in F127 (PLGA-PEG/F127) and made in P80 (PLGA-PEG/P80) have different fates within the developing brain (1). PLGA-PEG/F127 nanoparticles were 60.2 ± 0.8 nm, -2.6 ± 0.3 mV, and had a PDI of 0.18 ± 0.01. PLGA-PEG/P80 nanoparticles were 66.2 ± 1.4 nm, -1.98 ± 0.3 mV, and had a PDI of 0.19 ± 0.01. Following i.p. injection, serum concentration of PLGA-PEG nanoparticles was present at 1h and continued to increase and reach the maximum concentration by 4 h, with a half-life (t_1/2) of 5.89 h for PLGA-PEG/F127. The accumulation of PLGA-PEG nanoparticles in brain, heart and lung also reached the peak at around 4 h. Liver, spleen and kidney had a delayed particle accumulation in the first 4 h after injection and then reached peak concentrations at 24 h – no to minimal concentrations were detected at 72 h. Among all organs, liver accumulated the most nanoparticles, whereas heart, lung and kidney had relatively low accumulation (less than 5% injected dose), and spleen was intermediate. Additionally, PLGA-PEG nanoparticles formulated with different surfactants had different biodistributions, either at the tissue-level or organ-level. t_1/2 for PLGA-PEG/P80 was shorter than that of PLGA-PEG/F127. At the tissue level, PLGA-PEG/P80 accumulated in neurons and microglia in the brain, but PLGA-PEG/F127 remained associated with brain capillaries. There were minimal differences in distribution in other organs, suggesting a unique mechanism of PLGA-PEG/P80 interaction with the brain endothelium (2).

Conclusion: PLGA-PEG nanoparticles are very promising drug delivery vehicles for the neonatal population, especially in the field of brain disease and injury, where the dosage determination depends on the development of PK profiles of nanoparticles in neonates. Understanding the PK profiles and biodistribution, and associated residence time, of PLGA-PEG nanoparticles in neonates will help design therapeutic dosing regimens with maximum efficiency and minimum toxicity, and thus help improve the speed of clinical translation and drug safety of nanodrugs into this underserved population.

References: (1) Joseph A. et al, Biomaterials. 2021, 277: 121086. (2) Kreuter J. et al, J Drug. Target. 2002, 10(4): 317-325.

Presenter biography: Nuo Xu is a first-year PhD student in Chemical Engineering department of University of Washington in Seattle, US. She earned a MS at University of Washington. She carries out research in the fields of drug delivery, neonatal disease, and neuroscience.

Learning Objectives: (1) Understand the PK profile and biodistribution of PLGA-PEG nanoparticles in term-equivalent rats. (2) Evaluate the differences in PK profile and biodistribution of PLGA-PEG particles made in different surfactants.