Article

Mucus penetrating nanoparticles: biophysical tool and method of drug and gene delivery.

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.
Advanced Materials (Impact Factor: 15.41). 07/2012; 24(28):3887-94. DOI: 10.1002/adma.201201800
Source: PubMed

ABSTRACT A method that could provide more uniform and longer-lasting drug and gene delivery to mucosal surfaces holds the potential to greatly improve the effectiveness of prophylactic and therapeutic approaches for numerous diseases and conditions, including sexually transmitted infections, cystic fibrosis, chronic rhinosinusitis, inflammatory bowel disease, and glaucoma to name a few. However, the body's natural defenses, including adhesive, rapidly cleared mucus linings coating nearly all entry points to the body not covered by skin, has limited the effectiveness of drug and gene delivery by nanoscale delivery systems. This article discusses the recent development of the “mucuspenetrating particle” or “MPP” nanotechnology, and how it has been used to both enhance understanding of the nanoscale barrier properties of human mucus secretions, and to achieve more uniform and longer-lasting drug delivery to mucosal tissues following topical administration. Drug loaded MPPs possess non-adhesive coatings that allow them to rapidly penetrate mucus layers through openings in the mucus mesh at rates nearly as fast as they would penetrate pure water. Critically, MPPs allow enhanced drug and gene delivery to mucosal tissues without diminishing the protective function of mucus. Recent progress in the development of MPPs as a biophysical tool to probe the length-scale dependent rheological properties of mucosal secretions and as a method for drug and gene delivery is highlighted.

1 Follower
 · 
96 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The synthesis of nanocarriers with ‘‘slippery’’ surface (i.e., poly(lactide-co-glycolide)–polyethylene glycol (PLGA–PEG) nanoparticles (NPs) and polyelectrolyte complexes (PECs) of polyacrylic acid (PAA) with poly-L-lysine (PLL) and/or polyarginine (PArg)) and of nanocarriers (i.e., PLGA NPs, PLGA–PEG NPs, liposomes) containing a mucolytic agent (i.e., 4-mercaptobenzoic acid (4MBA)) is presented. Depending on the molecular weight (MW) of PEG (i.e., 2, 5 kDa), PLGA–PEG NPs with a ‘‘brush’’ or ‘‘dense brush’’ PEG configuration were prepared. The PLGA–PEG NPs exhibited increased mucus permeability in comparison with non-pegylated PLGA NPs when tested in fresh porcine intestinal mucus. The NPs that were prepared using PEG with a MW equal to 5 kDa and had a ‘‘dense brush’’ PEG configuration, were found to exhibit the highest mucus permeability. The average size and the surface charge of PECs could be effectively tuned by varying the PAA/polycation charge ratio, thus resulting in the synthesis of neutral as well as positively and negatively charged PECs. The PECs with negative surface charges were found to exhibit the highest mucus permeability followed by the neutral and finally the positively charged PECs. Depending on the initial concentration of the mucolytic agent, 4MBA loadings up to 13.65, 13.1 and 18.43 wt% were achieved for PLGA NPs, PLGA–PEG NPs and liposomes, respectively. PLGA and PLGA–PEG NPs were characterized by a rapid release of the mucolytic agent (i.e., >80 wt% of 4MBA was released in 20 min) whereas, its encapsulation in liposomes allowed a more controlled release (i.e., up to 30 wt% of 4MBA was released in 45 min). 4MBA loaded liposomes were found to exhibit increased mucus permeability depending on the composition of the phospholipid bilayer.
    European Journal of Pharmaceutics and Biopharmaceutics 02/2015; DOI:10.1016/j.ejpb.2015.01.021 · 4.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Delivering drugs to the colorectum by enema has advantages for treating or preventing both local and systemic diseases. However, the properties of the enema itself are not typically exploited for improving drug delivery. Sodium ions are actively pumped out of the lumen of the colon, which is followed by osmotically-driven water absorption, so we hypothesized that this natural mechanism could be exploited to drive nanoparticles and drugs to the colorectal tissue surface. Here, we report that sodium-based, absorption-inducing (hypotonic) enemas rapidly transport hydrophilic drugs and non-mucoadhesive, mucus penetrating nanoparticles (MPP), deep into the colorectal folds to reach virtually the entire colorectal epithelial surface. In contrast, isotonic and secretion-inducing (hypertonic) vehicles led to non-uniform, poor surface coverage. Sodium-based enemas induced rapid fluid absorption even when moderately hyper-osmolal (~350mOsm) compared to blood (~300mOsm), which suggests that active sodium absorption plays a key role in osmosis-driven fluid uptake. We then used tenofovir, an antiretroviral drug in clinical trials for preventing HIV, to test the effects of enema composition on local and systemic drug delivery. We found that strongly hypotonic and hypertonic enemas caused rapid systemic drug uptake, whereas moderately hypotonic enemas with ion compositions similar to feces resulted in high local tissue levels with minimal systemic drug exposure. Similarly, moderately hypotonic enemas provided improved local drug retention in colorectal tissue, whereas hypertonic and isotonic enemas provided markedly reduced drug retention in colorectal tissue. Lastly, we found that moderately hypotonic enema formulations caused little to no detectable epithelial damage, while hypertonic solutions caused significant damage, including epithelial sloughing; the epithelial damage caused increased systemic drug absorption and penetration of MPP into colorectal tissue, a potential advantage in certain drug delivery applications. In summary, we illustrate that enema composition can be adjusted to maximize local versus systemic drug delivery, and that mildly hypotonic, sodium-based vehicles can provide uniform drug and MPP delivery in the colon that maximizes local drug concentrations. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 04/2015; 209. DOI:10.1016/j.jconrel.2015.04.040 · 7.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There are an abundance of nanoparticle technologies being developed for use as part of therapeutic strategies. This review focuses on a narrow class of metal nanoparticles that have therapeutic potential that is a consequence of elemental composition and size. The most widely known of these are gold nanoshells that have been developed over the last two decades for photothermal ablation in superficial cancers. The therapeutic effect is the outcome of the thickness and diameter of the gold shell that enables fine tuning of the plasmon resonance. When these metal nanoparticles are exposed to the relevant wavelength of light, their temperature rapidly increases. This in turn induces a localized photothermal ablation that kills the surrounding tumor tissue. Similarly, gold nanoparticles have been developed to enhance radiotherapy. The high-Z nature of gold dramatically increases the photoelectric cross-section. Thus, the photoelectric effects are significantly increased. The outcome of these interactions is enhanced tumor killing with lower doses of radiation, all while sparing tissue without gold nanoparticles. Silver nanoparticles have been used for their wound healing properties in addition to enhancing the tumor-killing effects of anticancer drugs. Finally, platinum nanoparticles are thought to serve as a reservoir for platinum ions that can induce DNA damage in cancer cells. The future is bright with the path to clinical trials is largely cleared for some of the less complex therapeutic metal nanoparticle systems.For further resources related to this article, please visit the WIREs website.Conflict of interest: The authors have declared no conflicts of interest for this article.
    Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology 12/2014; DOI:10.1002/wnan.1322 · 4.24 Impact Factor