Excellence in Research: Elucidating the mechanisms that regulate cell uptake of homogeneous biodegradable polymeric nanoparticles to improve targeted therapeutic delivery

Over the past two decades, there has been a significant increase in therapeutics targeting multiple diseases, infections, and vaccines. However, many challenges are still being faced with therapeutic delivery to specific tissues and cells and high dosages causing unwanted side effects. Biodegradable polymeric nanoparticles offer many advantages for the delivery of therapeutic drugs and vaccines, such as cell and tissue targeting, slow-release, and reduced side effects to enhance the efficacy.

The goal of this project is to show that by using nanoparticles of similar size and shape, better cell uptake and delivery will result in improved efficacy. The innovativeness of this project has the potential to develop safe and novel therapeutics that are effective for many infectious diseases caused by bacteria, viruses, fungi, as well as cancers.

The project will provide research training and mentoring to underrepresented undergraduate and graduate students in STEM fields at Alabama State University from disciplines such as nanotechnology, immunology, cell biology, genomics, and proteomics. Students will also be provided other educational opportunities, including seminars, professional development training activities such as ethics in research, scientific writing, and presentations at scientific meetings.

The project will considerably strengthen the research and educational skills of students to bring diversity to the global workforce.

Endocytosis is one major route that regulates biodegradable polymeric nanoparticle uptake and transport mechanisms in biological systems for therapeutic delivery. Understanding the endocytosis mechanisms of nanoparticles is critical for effective therapeutic delivery and function, especially regarding their homogeneous and heterogeneous physical properties.

Much of what is known for the delivery of therapeutics comes from heterogeneous rather than homogeneous polymeric nanoparticles. Although both nanoparticle types may have distinct endocytosis mechanisms due to their physical properties, there is a paucity of data on the endocytosis mechanism regulating homogeneous nanoparticles' cellular uptake and impact on therapeutic delivery and function.

The hypothesis to be tested is that therapeutic delivery efficiency is dependent on the homogeneity of nanoparticles; homogeneous rather than heterogeneous nanoparticles will be more efficiently endocytosed to improve therapeutic delivery and function due to uniformity and distinct endocytosis mechanisms. This project will focus on intracellular protein targeting for delivery of a chlamydial bacterial protein encapsulated in poly D, L-lactide-co-glycolide, and poly(lactic acid)-poly(ethylene glycol to evaluate the interaction with dendritic cells as antigen-presenting cells in vitro and mice.

The objectives are: 1) to formulate and characterize the encapsulated protein to understand its interactions with dendritic cells leading to uptake and regulation of cellular function; 2) to decipher the specific endocytosis pathway exploited by the encapsulated protein of different size and formulation, 3) to determine the role of specific endocytosis pathways regulating the encapsulated protein uptake and therapeutic function in mice, and 4) to extend the dendritic cells findings to other cell lineages. The research will exploit various mechanistic approaches to unveil new knowledge leading to scientific discoveries to improve human health-related diseases.

The results will show how endocytosis differentially regulates the delivery of homogeneous and heterogeneous nanoparticles to enhance targeted delivery and therapeutic function. The new knowledge will enable scientists to develop efficient homogeneous size-specific intracellular nanocarriers for therapeutics targeting multipurpose biomedical applications.

The broader impact is that the findings will apply to more categories of nanoparticles, further advancing new scientific knowledge leading to novel nanotherapeutics impacting biomedical and biopharmaceutical applications. This project will also broaden the research infrastructure in nanotechnology and advance the mission of Alabama State University by providing quality education and cutting-edge skills to the underrepresented minority population in Alabama and the society at large.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.