Sustained release of peptides and proteins from polymeric nanocarriers produced by inverse Flash NanoPrecipitation

Chester E. Markwalter, Robert F. Pagels, Ava N. Hejazi, Kurt D. Ristroph, Jiping Wang, Ke Chen, Jian Li, Robert K. Prud'homme

Research output: Contribution to journalArticlepeer-review

Abstract

Peptide and protein therapeutics generally exhibit high potency and specificity and are increasingly important segments of the pharmaceutical market. However, their clinical applications are limited by rapid clearance and poor membrane permeability. Encapsulation of the peptide or protein into a nano-scale carrier can modify its pharmacokinetics and biodistribution. This might be employed to promote uptake in desired cell types or tissues, to limit systemic exposure, or to reduce the need for frequent injections. We have recently described inverse Flash NanoPrecipitation (iFNP), a scalable technique to encapsulate water-soluble therapeutics into polymeric nanocarriers, and have demonstrated improvements in therapeutic loading of an order of magnitude over comparable approaches. Here, we describe the formulation parameters that control release rates of encapsulated model therapeutics polymyxin B, lysozyme, and bovine serum albumin from nanocarriers produced using iFNP. Using a neutropenic lung infection mouse model with a multi-drug resistant Acinetobacter baumannii clinical isolate, we demonstrate enhanced therapeutic effect and safety profile afforded by nanocarrier-encapsulated polymyxin B following pulmonary administration. The encapsulated formulation reduced toxicity observed at elevated doses and resulted in up to 2.7-log10 reduction in bacterial burden below that of unencapsulated polymyxin B. These results establish the promise of iFNP as a platform for nanocarrier delivery of water-soluble therapeutics.

Original languageEnglish (US)
Pages (from-to)11-20
Number of pages10
JournalJournal of Controlled Release
Volume334
DOIs
StatePublished - Jun 10 2021

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Keywords

  • Antibiotics
  • Biologics
  • Nanocarriers
  • Nanoparticles
  • Pulmonary delivery
  • Sustained release

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