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A Possible Approach for Oral Drug Delivery of Nanoparticles COSMOS, Vol. 10, No. 1 (2014) 1–4 © World Scienti¯c Publishing Company DOI: 10.1142/S0219607714400035 A POSSIBLE APPROACH FOR ORAL DRUG DELIVERY OF NANOPARTICLES RABI'ATUL `ADAWIYAH BINTE MINHAT and THILO HAGEN Department of Biochemistry, Yong Loo Lin School of Medicine National University of Singapore, 117599 Singapore Received 12 February 2014 Revised 26 March 2014 Accepted 10 April 2014 Published 13 February 2015 Keywords: Oral drug delivery; nanoparticles; neonatal Fc receptor. Advances in biotechnology have led to numerous nanoparticles relative to the total atom number.2 discoveries and development of proteins and other These special properties are the reason why nano- macromolecules as pharmaceutical drugs.2 The particles have a wide variety of potential applica- production of macromolecules as therapeutics has tions in various ¯elds such as medicine, energy and improved treatment options in many areas in electronics industries. Thus, the development of an medicine. However, delivery of these macromolecule oral delivery system using nanoparticles is advan- COSMOS Downloaded from www.worldscientific.com drugs has mostly been restricted to parenteral tageous. If successful, the method could be combined methods of administration. The development of a with other techniques, such as a nanoparticle-based more convenient oral delivery system still faces many chemotherapy free of the debilitating side-e®ects,7,9 challenges. to further improve available treatment options. by NATIONAL UNIVERSITY OF SINGAPORE on 03/30/15. For personal use only. Many macromolecule drugs are vulnerable to the There have been several attempts to develop a pH variation and enzymatic degradation in the method for oral drug delivery using nanoparticles,2 gastrointestinal tract.2 One way to protect the drugs but these attempts have mostly had undesirable from degradation is by encapsulation.4 In particular, drawbacks. The extent to which a protein drug is encapsulation of drugs in nanoparticles (NPs) has absorbed into the bloodstream after administration, received considerable attention. Nanoparticles are or the bioavailability of the drug, still remain a microscopic particles that have at least one dimen- major challenge for oral delivery of macromolecules. sion measuring 100 nm or less.1 At the nanoscale, Normally, most clinically used drugs are absorbed the properties of many conventional materials through epithelial cells by transcellular passive dif- change.2 Unlike bulk materials, which are larger fusion.2 However, the largely hydrophilic nature of than one micrometer and have constant physical macromolecules prevents their crossing through the properties regardless of their size, nanoparticles ex- phospholipid bilayer of cell membranes.4 One ap- hibit special properties. These special properties in- proach to overcome this barrier made use of the clude surface e®ects and quantum e®ects and result ability of nanoparticles to target M-cells of Peyer's from the very small size of nanoparticles and the patches in the small intestine and the consequent signi¯cant percentage of atoms at the surface of the absorption of the nanoparticles by transcytosis.15 1 2 R. A. B. Minhat & T. Hagen While successful to an extent, Peyer's patches only side was observed with non-targeted nanoparticles. make up a speci¯c portion of the intestine, thus This suggests that conjugating Fc fragments to limiting the surface area for absorption. Another nanoparticles could be a viable approach for oral approach sought to increase the permeability of the delivery of nanomedicine. intestinal epithelium by using permeation enhancers The authors also quanti¯ed their observations by to target the tight junctions in between adjacent radiolabelling the nanoparticles with 14C. The bio- cells.13 This method, however, risks transport of not distribution measured in the spleen, kidneys, liver, only drugs into the bloodstream, but potentially heart and lungs showed that orally administered harmful substances as well. Hence, these drawbacks NP-Fc successfully entered the systemic circulation prompt further exploration into di®erent approa- and were able to reach several organs known to ches to develop an oral drug delivery system for express FcRn. Notably, the accumulation of 14C nanoparticles. measured in the organs was transient; the nano- In a paper recently published in Science Trans- particle accumulation peaked at 2.5 h after delivery lational Medicine, Pridgen et al. described a method before the nanoparticles were cleared from that could pave the way for a more convenient the organs. The basis for this pharmacodynamic oral administration of nanomedicine.10 The authors pro¯le warrants further attention. The absorption exploited the ability to easily manipulate the surface e±ciency calculated from the biodistribution data of nanoparticles. The surface of nanoparticles is showed that Fc-conjugated nanoparticles have a crucial to determining their properties such as sta- higher absorption e±ciency than non-targeted bility, solubility and cell type speci¯c uptake.14 nanoparticles by 11.5 fold. It is worth mentioning Taking advantage of this property, Pridgen et al. that not all organs expressing FcRn were measured decided to conjugate immunoglobulin G (IgG) Fc in the experiment, and 14C-labelled nanoparticles fragments to the surface of nanoparticles. Based on may also be freely circulating in the blood. Thus, the previous evidence of the neonatal receptor (FcRn) absorption e±ciency may actually be higher than mediating the transcytosis of nanoparticles across a what was calculated. However, for this method of monolayer of epithelial cells,6,16 the authors hypo- delivery to be on par or as e®ective as intravenous thesised that Fc-conjugated nanoparticles (NP-Fc) administration, which boasts 100% bioavailability, would be targeted to the FcRn and be transported further studies may be required to improve the ab- across the intestine epithelium. sorption e±ciency. COSMOS Downloaded from www.worldscientific.com FcRn is a neonatal receptor that is important Having demonstrated that oral delivery is suc- during postnatal development by mediating the in- cessful by modifying the nanoparticle surface with testinal uptake of IgG from breast milk by the o®- Fc fragments, Pridgen et al. then showed that this spring. Of note, FcRn is also expressed at similar method remains viable when drugs are encapsulated 5 by NATIONAL UNIVERSITY OF SINGAPORE on 03/30/15. For personal use only. levels in adults. FcRn binds to the Fc portion of within the modi¯ed nanoparticles. Nanoparticles IgG with high a±nity in acidic ðpH < 6:5Þ but not encapsulating insulin (insNPs) were developed and physiological environments ðpH 7:4Þ.11 Thus, in the observed insulin release pro¯le in vitro showed the intestine, NP-Fc would bind to FcRn on the that all the insulin was released before 10 h. Since apical surface and be taken up by endocytosis.12 nanoparticles have been shown to be cleared from During intracellular tra±cking, the acidic endosome our system after 10 h,10 the insulin release pro¯le would ensure the continued interaction between observed is favourable as it would mean that all NP-Fc and FcRn.3 Upon reaching the basolateral the insulin would be delivered before complete side, however, exocytosis and exposure to a neutral clearance. Furthermore, when the insulin released pH would cause the release of the NP-Fc,8 which will in vitro was injected into the tail vein of mice, a then enter systemic circulation. hypoglycemic response was elicited. After con- Using °uorescently labelled nanoparticles, the ¯rming the function of the insNPs, the authors authors demonstrated that Fc-conjugated nano- showed that, consistent with their previous particles were able to cross the intestinal epithelium. results, insNPs targeted to FcRn (insNP-Fc) were When labelled NP-Fc were orally administered to able to generate a signi¯cant hypoglycemic re- wild-type mice, °uorescence was observed inside the sponse upon oral administration. In comparison, villi on the basolateral side of intestinal epithelial non-targeted insNP produced a response similar cells. However, no °uorescence on the basolateral to that of the negative controls, which were orally A Possible Approach for Oral Drug Delivery of Nanoparticles 3 administered free insulin and NP-Fc without in- References sulin. These results suggest that targeting nano- 1. Buzea C, Pacheco I and Robbie K, Nanomaterials particles to FcRn is a feasible approach to oral and nanoparticles: Sources and toxicity, Biointer- drug delivery. phases 2(4):17–71, 2007. There are a number of additional aspects that 2. Chen M, Sonaje K, Chen K and Sung H, A review of makes the FcRn receptor targeted nanoparticle ap- the prospects for polymeric nanoparticle platforms in proach stand out. For instance, the authors reported oral insulin delivery, Biomaterials 32(36):9826– that the dose of insulin encapsulating NP-Fc re- 9838, 2011. quired to generate the hypoglycemic response was 3. Dickinson B, Claypool S, D'angelo J, Aiken M, markedly lower than other nanoparticle-based oral Venu N, Yen E, Wagner J, Borawski J, Pierce A, insulin delivery systems.2 Furthermore, the oral Hershberg R, Blumberg R and Lencer W, Ca2þ insNP-Fc was shown to produce a prolonged hypo- -dependent calmodulin binding to FcRn a®ects glycemic response of 15 h compared to 1.5 h with immunoglobulin G transport in the transcytotic pathway, Mol. Biol. Cell 19(1):414–423, 2008. injected insulin. 4. Goldberg M and Gomez-Orellana I, Challenges for The idea that any molecule, when encapsulated the oral delivery of macromolecules, Nature Reviews, in nanoparticles, could be tra±cked across the Drug Discovery 2(4):289–295, 2003. epithelial barrier has many positive implications in 5. Israel E, Taylor S, Wu Z, Mizoguchi E, Blumberg R, medicine. The results by Pridgen et al. demon- Bhan A and Simister N, Expression of the neonatal strate that the FcRn-mediated drug delivery ap- Fc receptor, FcRn, on human intestinal epithelial proach is successful with monolayers of Caco-2 cells, Immunology 92(1):69–74, 1997.
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