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: 17.49). 07/2012; 24(28):3887-94. DOI: 10.1002/adma.201201800
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.
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- "Nevertheless, the design of inhalable NP-based formulations is a demanding task . First, tailoring NP size and surface is fundamental to allow efficient crossing of cellular (biofilm bacteria) and extracellular (mucus) pulmonary barriers   . Then, appropriate engineering of NPs to be delivered by either nebulizers or the most advanced dry powder inhalers (DPIs) is an absolute need to reach the target at lung level. "
ABSTRACT: Cationic antimicrobial peptides (CAMPs) are very promising in the treatment of multi-drug resistant Pseudomonas aeruginosa lung infections experienced by cystic fibrosis (CF) patients. Nevertheless, there is an urgent need of inhalable formulations able to deliver the intact CAMP in conductive airways and to shield its interactions with airway mucus/bacterial biofilm, thus enhancing CAMP/bacteria interactions. Along these lines, the aim of this work was the design and development of nano-embedded microparticles (NEM) for sustained delivery of CAMPs in the lung. To this purpose, nanoparticles (NPs) made of poly(lactide-co-glycolide) (PLGA) containing a model CAMP, colistin (Col), were produced by emulsion/solvent diffusion technique. Engineering NPs with chitosan (CS) and poly(vinyl alcohol) (PVA) allowed to modulate surface properties and, in so doing, to improve NP transport through artificial CF mucus. In order to achieve a long-term stable dosage form useful for NP inhalation, NPs were spray-dried in different carriers (lactose or mannitol), thus producing NEM. The most promising NEM formulations were selected on the basis of bulk and flow properties, distribution of NPs in the carrier and aerosolization performance upon delivery through a breath-actuated dry powder inhaler. Of note, selected Col-loaded NEM were found to kill P. aeruginosa biofilm and to display a prolonged efficacy in biofilm eradication compared to the free Col. This effect was likely ascribable to the ability of NPs to penetrate into bacterial biofilm, as demonstrated by confocal analysis, and to sustain Col release inside it. Taken all together, our results indicate that adequate engineering of PLGA NPs represents an enticing technological approach to harness novel antimicrobials for P. aeruginosa lung infection, such as CAMPs, especially in CF. Copyright © 2015 Elsevier B.V. All rights reserved.
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- "A major obstacle to efficient treatment of P. aeruginosa infections is its ability to form biofilms in which bacteria are protected from defensive attacks by the immune system as well as xenobiotics. Moreover, biofilm colonies are entrapped in the pulmonal mucus layer, which most free drugs cannot penetrate readily due to interactions with anionic and hydrophobic mucus components (Cheow and Hadinoto, 2012b; Ensign et al., 2012). "
ABSTRACT: We evaluated an analytical setup to identify optimal preparation conditions for nanoplex formation of small molecule drugs and polyelectrolytes using ciprofloxacin (CIP) and dextran sulfate (DS) as model compounds. The suitability of isothermal titration calorimetry (ITC) as a screening tool for rational formulation optimization was assessed. Besides ITC, static and dynamic light scattering, zeta potential measurements and scanning electron microscopy were applied to analyze the influence of different salt types and ionic strengths on CIP/DS nanoplex formation. The addition of low amounts of salt, especially 0.1M NaCl, improved the formation of CIP/DS nanoplexes. The presence of low amounts of salt led to smaller and more numerous particles of higher uniformity but had no influence on the release of CIP from nanoplexes. Furthermore, the molar range, within which efficient complexation was achieved, was broader in the presence of 0.1M NaCl than in the absence of salt with overall comparable complexation efficiency. Importantly, binding affinity correlated with particle shape and morphology, potentially enabling optimization of critical quality attributes based on ITC data. Altogether, ITC along with supplemental methods is a versatile screening tool for the evaluation of nanoplex formulation conditions regarding mixing ratio, salt type and ionic strength. Copyright © 2015. Published by Elsevier B.V.
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- "The mucus barrier contains distinct layers and is composed mainly of heavily glycosylated proteins called mucins, which have the potential to block the absorption of certain nanoformulations. Modifications can be made to produce nanoformulations with increased mucus-penetrating properties (Ensign et al., 2012). Once the mucus coating has been traversed, the transport of nanoformulations across intestinal epithelial cells can be regulated by several steps, including cell surface binding, endocytosis, intracellular trafficking and exocytosis, resulting in transcytosis (transport across the interior of a cell) with the potential involvement of multiple subcellular structures. "
ABSTRACT: The delivery of therapeutic agents is characterised by numerous challenges including poor absorption, low penetration in target tissues and unspecific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterised by several challenges. The integration of property-distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterisation of nanoformulations with optimal pharmacokinetics.
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