Hydrophilic antibiotics encapsulated into nanoparticles for improved administration

K. Ristroph, P. Rummaneethorn, R. Prud'homme
Princeton University,
United States

Keywords: drug delivery, peptides, biologics, hydrophobic ion pairing, antibiotics


The global antibiotic resistance crisis looms as more multidrug-resistant (MDR) strains of bacteria continue to evolve. These MDR bacteria have overcome many traditional small-molecule traditional antibiotics and infect over 2 million patients in the U.S. annually. Worse, few new antibiotics available to fight MDR bacteria. Researchers have designed next-generation peptide antibiotics, which are significantly more potent against their target bacteria – even resistant strains – than small-molecule drugs. These peptides are part of the fastest-growing sector of the pharmaceutical market and are expected exceed $48 billion in value by 2025. By 2015, the FDA had approved over 60 peptide drugs. In 2017, 140 peptides were in clinical trials, with over 500 more in preclinical development. But administering these peptide drugs remains a challenge. Peptides are degraded in the stomach and cannot be administered orally. Other dosing routes, like injection or inhalation, present their own challenges. Physiological barriers like rapid blood clearance (when injected) or sticky lung mucus (when inhaled) chemically or physically keep peptide antibiotics from reaching their targets and working as designed. As a result, frequent dosing is required for efficacy – doing so is expensive, uncomfortable, and wasteful. Protecting peptides within administrative vehicles could significantly improve administration and delivery. A number of approaches – nanoparticles, liposomes, etc. – have been proposed to protect peptides, but processing the drugs into these delivery vehicles remains a major hurdle. Typical peptide delivery vehicles are composed of only 1-2% drug, and half of the total antibiotic is lost during processing. We herein describe a method to efficiently encapsulate peptides within polymeric nanoparticles. We employ Flash NanoPrecipitation (FNP), a simple and scalable technique for encapsulating hydrophobic drugs into polymeric nanoparticles (NPs) for protection and improved administration. Antibiotic peptides, which are hydrophilic, could not be encapsulated into nanoparticles via FNP. To expand the platform to hydrophilic therapeutics, we have recently coupled the technique of hydrophobic ion pairing (HIP) to FNP; our combined technique, HIP-FNP, reversibly makes charged hydrophilic molecules, including peptides, hydrophobic and encapsulates them into nanoparticles in a single step. The process works by reversibly making hydrophilic therapeutics into hydrophobic salts. This takes place at the same time nanoparticles are being made, so the resulting salts nucleate and form monodisperse nanoparticles. Inside the body, the process reverses, and the original antibiotic is controllably released from its protective nanoparticle. Using HIP-FNP, we have successfully encapsulated more than ten hydrophilic molecules, including antibiotic peptides, proteins, and small molecules. Our nanoparticles have loadings of 30-50% and encapsulation efficiencies over 95%. In addition, we have shown that we can tune the release rates of our encapsulated therapeutics by altering the species or amount of hydrophobic counterion introduced into the system. We believe this straightforward process offers a scalable and industrially-relevant method of improving the delivery of critical hydrophilic therapeutics, which previously were difficult to administer.