Nanoparticles slip through mucus barrier to protect against herpes virus

“Thick, sticky mucus layers limit effectiveness of drug delivery to mucosal tissues. Mucus-penetrating particles or MPPs (in red) are able to penetrate mucus, covering the entire surface of the mouse vagina (in blue). Improved distribution and retention of MPPs led to significantly increased protection in a mouse model for herpes simplex virus infection. Image by Laura Ensign.

Johns Hopkins researchers say they have demonstrated for the first time, in animals, that nanoparticles can slip through mucus to deliver drugs directly to tissue surfaces in need of protection.

The researchers used these mucus-penetrating particles, or MPPs, to protect against vaginal herpes infections in mice. The goal is to create similar MPPs to deliver drugs that protect humans against sexually transmitted diseases or even treat cancer.

“This is the first in vivo proof that MPPs can improve distribution, retention, and protection by a drug applied to a mucosal surface, said Justin Hanes, Ph.D., a professor of ophthalmology at the Johns Hopkins Wilmer Eye Institute and director of the Center for Nanomedicine at the Johns Hopkins University School of Medicine.

Hanes also is a principal investigator with the Johns Hopkins Center of Cancer Nanotechnology Excellence. Results of his team’s experiments are described in the June 13 issue of the journal Science Translational Medicine.

The moist mucosal surfaces of the body, like the eyes, lungs, intestines and genital tract, are protected from pathogens and toxins by layers of moist sticky mucus that is constantly secreted and shed, forming our outermost protective barrier.

“Although many people associate mucus with disgusting cold and cough symptoms, mucus is in fact a sticky barrier that helps keep you healthy,” says Laura Ensign, a doctoral student affiliated with the Center for Nanomedicine at the School of Medicine and with the Department of Chemical and Biomolecular Engineering at Johns Hopkins’ Whiting School of Engineering. She is the lead author of the journal report.

Unfortunately, Ensign noted, mucus barriers also stop helpful drug delivery, especially conventional nanoparticles intended for sustained drug delivery. In a Johns Hopkins laboratory, researchers developed nanoparticles that do not stick to mucus so they can slip through to reach the cells on the mucosal surface, in this case the surface of the mouse vagina, she added.

Ensign explained that conventional nanoparticles actually stick to mucus before releasing their drug payload and are then removed when the mucus is replenished, often within minutes to hours. Working with researchers in the laboratory of Richard Cone, Ph.D., in the Department of Biophysics in the university’s Krieger School of Arts and Sciences, the Hanes team fabricated particles with surface chemistry that mimics a key feature of viruses that readily infect mucosal surfaces.

“Richard Cone’s lab found that viruses, such as the human papilloma virus, could diffuse through human cervical mucus as fast as they diffuse through water. These ‘slippery viruses’ have surfaces that are ‘water-loving,’ ” Hanes said. “In contrast, many nanoparticles intended to deliver drugs to mucosal surfaces are ‘mucoadhesive’ and ‘oil-loving,’ but these nanoparticles stick to the superficial layers of the mucus barrier, the layers that are most rapidly removed.”

To make their mucus-penetrating particles, the team transformed conventional ‘oil-loving’ nanoparticles by coating them with a substance used in many commercial pharmaceutical products:¬†polyethylene glycol. PEG makes the particles “water-loving,” like the viruses that slip right through mucus.

“The key is that the nanoparticles, like viruses, have to be small enough to go through the openings in the mucus mesh, and also have surfaces that mucus can’t stick to. If you think about it,” said Ensign, “mucus sticks to almost everything.”

“Viruses have evolved over millions of years to become slippery pathogens that readily penetrate our protective mucus barriers,” said Cone, “and engineering nanoparticles that penetrate the mucus barrier just like viruses is proving to be a clever way to deliver drugs.”

Hanes emphasized that the MPPs provided greatly improved protective efficacy while at the same time reducing the effective dose of drug needed 10-fold. Furthermore, Hanes added, the MPPs “continue to supply drug for at least a day and provide nearly 100 percent coverage of the mucosal surface of the vagina and ectocervix” in their laboratory mice.

“We’ve shown that mucus-penetrating particles are safe for vaginal administration in mice. Our next move will be to show that they are safe for vaginal administration in humans,” Ensign said. “Now our laboratory currently is working on an MPP formulation of a drug that protects against HIV infection that we hope will be tested in humans.”

Their technology could lead to a once-daily treatment for preventing sexually transmitted diseases, for contraception and for treatment of cervico-vaginal disorders, Ensign said.

Ensign added that MPP technology has the potential to prevent a wide range of mucosal diseases and infections, including chronic obstructive pulmonary disease, lung cancer, and cystic fibrosis,” Ensign said.

Additional authors on the paper include postdoctoral fellow Ying-Ying Wang and research specialist Timothy Hoen from the Department of Biophysics; former master’s student Terence Tse from the Department of Chemical and Biomolecular Engineering; and Benjamin Tang, formerly of Johns Hopkins School of Medicine and currently at the Massachusetts Institute of Technology.

Under a licensing agreement between Kala Pharmaceuticals and the Johns Hopkins University, Hanes is entitled to a share of royalties received by the university on sales of products used in the study.

Hanes and the university own Kala Pharmaceuticals stock, which is subject to certain restrictions under university policy. Hanes is also a founder, a director and a paid consultant to Kala Pharmaceuticals. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.”

Story by Mary Spiro

Additional news coverage of this research may be found at the following links:

Phys.org

WYPR: The Mucus Ruse

Scientific American