Nanoparticle Transport in Epithelial Cells: Pathway Switching Through Bioconjugation

Non-invasive delivery of biotherapeutics, as an attractive alternative to injections, could potentially be achieved through the mucosal surfaces, utilizing nanoscale therapeutic carriers. However, nanoparticles do not readily cross the mucosal barriers, with the epithelium presenting a major barrier to their translocation. The transcytotic pathway of vitamin B12 has previously been shown to ‘ferry’ B12-decorated nanoparticles across intestinal epithelial (Caco-2) cells. However, such studies have not been reported for the airway epithelium. Furthermore, the presence in the airways of the cell machinery responsible for transepithelial trafficking of B12 is not widely reported. Using a combination of molecular biology and immunostaining techniques, our work demonstrates that the bronchial cell line, Calu-3, expresses the B12-intrinsic factor receptor, the transcobalamin II receptor and the transcobalamin II carrier protein. Importantly, the work showed that sub-200 nm model nanoparticles chemically conjugated to B12 were internalised and transported across the Calu-3 cell layers, with B12 conjugation not only enhancing cell uptake and transepithelial transport, but also influencing intracellular trafficking. Our work therefore demonstrates that the B12 endocytotic apparatus is not only present in this airway model, but also transports ligand-conjugated nanoparticles across polarised epithelial cells, indicating potential for B12-mediated delivery of nanoscale carriers of biotherapeutics across the airways.

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“…size and surface charge determination pre- and post-B 12 conjugation) was described in a recent publication by our group [18].…”

Section: Methodsmentioning

confidence: 99%

Uptake and transport of B 12 -conjugated nanoparticles in airway epithelium

Fowler

Vllasaliu

Falcone

et al. 2013

Journal of Controlled Release

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“…Interestingly, conjugating vitamin B12 to NPs causes a switch in the transcytosis pathway used to cross the enterocytes. Studies have shown that vitamin B12-NP conjugates are able to avoid trafficking through lysosomes, while either vitamin B12 or non-targeted NPs pass through lysosomes in Caco-2 in vitro models [97]. Targeting of NPs to this pathway by conjugating vitamin B12 to the NP surface has been successful in delivering biologics to the bloodstream.…”

Section: Strategies For Oral Deliverymentioning

confidence: 99%

Polymeric nanoparticle drug delivery technologies for oral delivery applications

Pridgen¹,

Alexis²,

Farokhzad³

2015

Expert Opinion on Drug Delivery

213

128

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Introduction Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles are one technology being developed to enable clinically feasible oral delivery. Areas covered This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal barriers using polymeric nanoparticles will be considered, including mucoadhesive biomaterials and targeting of nanoparticles to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations. Expert opinion There have been many approaches used to overcome the transport barriers presented by the gastrointestinal tract, but most have been limited by low bioavailability. Recent strategies targeting nanoparticles to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and nanoparticles across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric nanoparticle technologies and enable the translation of these technologies to clinical practice.

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“…NPs have been designed to target this pathway by conjugating vitamin B12 to the surface of biologic-loaded NPs. Studies with insulin-loaded NPs targeted to the vitamin B12 receptor have demonstrated enhanced absorption of insulin after oral administration 47–49 .…”

Section: Resultsmentioning

confidence: 99%

Polymeric Nanoparticle Technologies for Oral Drug Delivery

Pridgen

Alexis

Farokhzad

2014

Clinical Gastroenterology and Hepatology

126

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Biologics are being increasingly used for the treatment of many diseases. These treatments typically require repeated doses administered by injection. Alternate routes of administration, particularly oral, are considered favorable because of improved convenience and compliance by patients, but physiological barriers such as extreme pH, enzyme degradation, and poor intestinal epithelium permeability limit absorption. Encapsulating biologics in drug delivery systems such as polymeric nanoparticles (NPs) prevents inactivation and degradation caused by low pH and enzymes of the gastrointestinal (GI) tract. However, transport across the intestinal epithelium remains the most critical barrier to overcome for efficient oral delivery. This review focuses on recent advances in polymeric NPs being developed to overcome transport barriers and their potential for translation into clinical use.

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Nanoparticle Transport in Epithelial Cells: Pathway Switching Through Bioconjugation

Cited by 43 publications

References 69 publications

Uptake and transport of B 12 -conjugated nanoparticles in airway epithelium

Uptake and transport of B 12 -conjugated nanoparticles in airway epithelium

Polymeric nanoparticle drug delivery technologies for oral delivery applications

Polymeric Nanoparticle Technologies for Oral Drug Delivery

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