Microparticle Depots for Controlled and Sustained Release of Endosomolytic Nanoparticles

Abstract

Introduction

Nucleic acids have gained recognition as promising immunomodulatory therapeutics. However, their potential is limited by several drug delivery barriers, and there is a need for technologies that enhance intracellular delivery of nucleic acid drugs. Furthermore, controlled and sustained release is a significant concern, as the kinetics and localization of immunomodulators can influence resultant immune responses. Here, we describe the design and initial evaluation of poly(lactic-co-glycolic) acid (PLGA) microparticle (MP) depots for enhanced retention and sustained release of endosomolytic nanoparticles that enable the cytosolic delivery of nucleic acids.

Methods

Endosomolytic p[DMAEMA]10kD-bl-[PAA0.3-co-DMAEMA0.3-co-BMA0.4]25kD diblock copolymers were synthesized by reversible addition-fragmentation chain transfer polymerization. Polymers were electrostatically complexed with nucleic acids and resultant nanoparticles (NPs) were encapsulated in PLGA MPs. To modulate release kinetics, ammonium bicarbonate was added as a porogen. Release profiles were quantified in vitro and in vivovia quantification of fluorescently-labeled nucleic acid. Bioactivity of released NPs was assessed using small interfering RNA (siRNA) targeting luciferase as a representative nucleic acid cargo. MPs were incubated with luciferase-expressing 4T1 (4T1-LUC) breast cancer cells in vitro or administered intratumorally to 4T1-LUC breast tumors, and silencing via RNA interference was quantified via longitudinal luminescence imaging.

Results

Endosomolytic NPs complexed to siRNA were effectively loaded into PLGA MPs and release kinetics could be modulated in vitro and in vivovia control of MP porosity, with porous MPs exhibiting faster cargo release. In vitro, release of NPs from porous MP depots enabled sustained luciferase knockdown in 4T1 breast cancer cells over a five-day treatment period. Administered intratumorally, MPs prolonged the retention of nucleic acid within the injected tumor, resulting in enhanced and sustained silencing of luciferase relative to a single bolus administration of NPs at an equivalent dose.

Conclusion

This work highlights the potential of PLGA MP depots as a platform for local release of endosomolytic polymer NPs that enhance the cytosolic delivery of nucleic acid therapeutics.

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Abbreviations

BMA:

Butyl methacrylate

DCM:

Dichloromethane

DMAEMA:

Dimethylaminoethyl methacrylate

D-PDB:

Poly[DMAEMA]10kD-block-[PAA0.3-co-DMAEMA0.3-co-BMA0.4]25kD

ECT:

4-Cyano-4-(ethylsulfanylthiocarbonyl)sulfanylpentanoic acid

MP:

Microparticle

NP:

Nanoparticle

PAA:

Propylacrylic acid

PLGA:

Poly(lactic-co-glycolic) acid

PVA:

Polyvinyl alcohol

SEM:

Scanning electron microscopy

V-70:

2,2′-Azobis(4-methoxy-2,4-dimethyl valeronitrile)

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Acknowledgments

We gratefully acknowledge Dr. Bob Weinberg and Dr. Didier Trono for gifts of plasmids via Addgene.org. We thank Dr. Steven Goodbred Jr. and his laboratory for use of the Mastersizer 2000 (Malvern, USA). We thank Kyle Becker for his assistance with the orthotopic tumor inoculations. We thank the core facilities of Vanderbilt, including the Vanderbilt Institute of Nanoscale Sciences and Engineering (VINSE) for the use of both the Zetasizer Nano ZS Instrument (Malvern, USA) and the Zeiss Merlin SEM (Carl Zeiss Microscopy, LLC, ZEISS Group, Thornwood, NY), the Vanderbilt Translational Pathology Shared Resource (supported in part by the NCI/NIH Cancer Center Support Grant 5P30 CA684850-19) for cryosectioning of tumor samples, and Vanderbilt University Medical Center Flow Cytometry Shared Resource (supported by the Vanderbilt Ingram Cancer Center P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404) for cell sorting. This research was supported by grants from Alex’s Lemonade Stand Foundation ‘A’ Award SID924 (JTW) and Pediatric Oncology Student Training (POST) Award cosponsored by Love Your Mellon (KMG), the American Cancer Society Institutional Research Grant IRG-58-009-56 (JTW), the Congressionally-Directed Medical Research Program W81XWH-161-0063 (JTW) and W81XWH-161-0063 (RSC), the National Institutes of Health R01CA224241 (CLD) and R01EB019409 (CLD), and the National Science Foundation Graduate Research Fellowship Program 0909667 and 1445197 (KVK).

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

All animal experiments were approved by the Vanderbilt University Institutional Animal Care and Use Committee (IACUC), and all surgical and experimental procedures were performed in accordance with the regulations and guidelines of the Vanderbilt University IACUC. Female BALB/cJ mice (6–8 weeks old; The Jackson Laboratory, Bar Harbor, ME) were maintained at the animal facilities of Vanderbilt University under specific pathogen-free conditions. Tumor volume, total mass, and animal well-being were monitored every other day.

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John T. Wilson is an Assistant Professor of Chemical and Biomolecular Engineering and Biomedical Engineering at Vanderbilt University. He received his B.S. in Bioengineering from Oregon State University and his Ph.D. from the Georgia Institute of Technology in the laboratory of Professor Elliot L. Chaikof, where he was awarded a Whitaker Foundation Graduate Fellowship. He then joined the laboratory of Professor Patrick Stayton at the University of Washington with support of a Cancer Research Institute Postdoctoral Fellowship. He started his independent laboratory at Vanderbilt in January of 2014, where his group works at the interface of molecular engineering and immunology to innovate technologies to improve human health. His multidisciplinary research program is supported by productive and synergistic collaborations with oncologists, cancer biologists, immunologists, chemists, and other engineers. Since establishing his lab at Vanderbilt, he has been awarded the NSF CAREER Award, an ‘A’ Award from Alex’s Lemonade Stand Foundation, a Melanoma Research Alliance Young Investigator Award, an Innovative Research Grant from Stand Up To Cancer, and has been named an Emerging Investigator by Biomaterials Science.

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This article is part of the 2019 CMBE Young Innovators special issue.

Associate Editor Michael R. King oversaw the review of this article.

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Garland, K.M., Sevimli, S., Kilchrist, K.V. et al. Microparticle Depots for Controlled and Sustained Release of Endosomolytic Nanoparticles. Cel. Mol. Bioeng. 12, 429–442 (2019). https://doi.org/10.1007/s12195-019-00571-6

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Keywords

  • Nucleic acid therapeutics
  • Local delivery
  • Intratumoral
  • Immunotherapy
  • RNA interference
  • Endosomal escape
  • PLGA
  • Biomaterial
  • Drug delivery depot