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Milk Components Offer Safe Options for Targeted Drug Delivery

    BCAA amino acid tablets, a glass of milk protein shake and hand weights that may be involved in drug delivery via milk proteins

    Written by: Anna Petherick, Ph.D. | Issue # 90 | 2019

    • Researchers are investigating several kinds of protein found in milk for their ability to carry medicines to specific parts of the digestive tract.
    • Casein proteins are apt for delivering molecules to the stomach, to treat gastric diseases.
    • β–Lactoglobulin, the main constituent of whey, can protect medicines from stomach acid, and offers a means to carry them unharmed to the intestines for absorption into the blood.

    Milk has evolved through mammalian history as a soup of complex molecules that provide nutrients, as well as developmental and immunological support to infants. Some of these complex molecules have been naturally selected for their abilities to deliver bioactive compounds in such a way that the infant body can make use of them. This involves, for example, the ability to bind ions with positive and negative charges, such as iron and calcium ions, respectively—and protecting delicate compounds from stomach acids so they can be absorbed through the intestinal wall. In short, some of the soup of complex molecules in milk are ready-made nano-scale delivery units that could be harnessed by science to carry modern medicines into the body to precise locations.

    Researchers are already tapping milk’s chemistry for safe molecular mules to transport pharmaceuticals and dietary supplements into the human body. The main proteins they have to work with are of two categories: caseins and whey proteins. Caseins—which make up 79% of milk’s total protein [1]—are a family of proteins that, in a watery solution, naturally organize themselves into spheres, called micelles. For the young infant this means that caseins are able to provide lots of calcium in addition to the nutritionally essential amino acids of which they are composed [1]. The fine details of how exactly casein micelles interact with calcium are still debated, but it is thought that small casein micelles bind to colloidal lumps of calcium phosphate and then group together [2].

    For an infant, caseins’ structures allows calcium phosphate to be released and then coagulate in the stomach. This is because caseins are rich in an amino acid called proline, which contributes to the interactions—or bonds—that hold together casein micelles, creating a relatively open structure that is accessible to stomach enzymes [1]. To the researcher looking for a safe way to target pharmaceuticals to the stomach, for example to treat gastric diseases, caseins offer a potentially very useful vehicle. Moreover, work to date shows that it is possible to bond nutraceuticals and synthetic drugs to casein proteins using various laboratory techniques, from heat-gelation to “polyelectrolyte ionic complexation” [1].

    However, some of the most notable progress in this field has focused on the other main protein category in milk. Whey proteins, which comprise 19% of milk’s total protein and are a waste product of cheese-making, are mostly made of up the proteins β-lactoglobulin and α-lactalbumin [1]. It is the former of these that is currently exciting researchers. In some ways, β-lactoglobulin is a complementary tool in the drug delivery toolkit to caseins. It is stable to the acid environment of the stomach, and so has the potential to protect otherwise delicate molecules through that gauntlet of the gut, enabling them to be released later in the digestive process. Moreover, like caseins, there are options for chemically linking β-lactoglobulin to molecules that one might wish to carry into the body, and it can bind to hydrophobic molecules (that is, oil-loving, as opposed to water-loving chemical structures) [1].

    The efforts of several groups of researchers have recently demonstrated the potential for taking advantage of β-lactoglobulin’s chemical characteristics. One group, based in China and South Korea, has made progress using it to enable the slow release of a component of green tea with anti-oxidant properties, called epigallocatechin gallate (EGCG) [3]. EGCG is normally given as a supplement encapsulated in chitosan, a long-chained carbohydrate molecule made from treating crustacean shells with a strong alkali. The reason for using chitosan is that it sticks to the walls of the intestine, allowing what’s left of the EGCG by that point in digestion to hang around in the intestines for longer. Only from there can EGCG be absorbed into the blood, and thereafter, as it circulates around the body, ward-off cancer and have other positive health effects that are linked to anti-oxidants.

    The existing problem with delivering EGCG in this way is that chitosan does little to protect it from the ravishes of stomach acid. This is why Jin Liang of Anhui Agricultural University’s “State Key Laboratory of Tea Plant Biology and Utilization” in Hefei, China, and colleagues, decided to try coating it in both chitosan and β-lactoglobulin. They compared their double-layered approach with the usual chitosan coating in a series of laboratory experiments intended to allow them to evaluate changes to EGCG availability over the course of a mimicked digestive process.

    They mimicked the stomach by adding pig pepsin and acid in a shaking water bath. Then they continued the shaking, increased the pH from 5.3 to a more neutral 6.8 by adding sodium hydroxide, and injected lipase, pancreatin, and bile extract from pig pancreas. Only after all of this physical and chemical processing would the chitosan-EGCG samples—and the chitosan-EGCG encased in β-lactoglobulin—be in the kind of state that they would be in after travelling through the small intestine. β-Lactoglobulin is degraded by pancreatic enzymes, so at this point it, too, would have been stripped away.

    After analyzing samples drawn from all along the mimicked digestive process, the researchers concluded that pepsin-resistant outer layer of β-lactoglobulin helps chitosan-EGCG complexes reach the intestines relatively unscathed. As a result, the amount of EGCG left to be released in the intestines was higher. Furthermore, when they arrived in the intestines, the chitosan chains that had adhered to the β-lactoglobulin were more exposed—having had the β-lactoglobulin stripped off—than they otherwise would have been, which prolonged the length of time for EGCG absorption because the exposed chitosan proved even better at sticking to the intestinal wall.

    The targeting of drug delivery that β-lactoglobulin makes possible is also being exploited by pharmaceutical researchers, Vilasinee Hirunpanich Sato, of Mahidol University in Bangkok, and Hitoshi Sato, of Showa University in Tokyo. Rather than EGCG, they are looking to deliver the immunosuppressive drug cyclosporin A to the intestines for absorption, using β-lactoglobulin as a gastric-juice shield. Currently, synthetic absorption enhancers are used to target cyclosporin A, and there is concern that these may have toxic side-effects.

    So far, the pair’s experiments feeding rats have been promising. The results have shown that using β-lactoglobulin instead of synthetic alternatives provides gastrointestinal absorption of the drug, and faster absorption as well [4]. In a paper published in the International Journal of Drug Delivery, they propose that other researchers view their experiments as a proof of concept for deploying β-lactoglobulin to carry all kinds of orally-delivered lipophilic medicines (drugs that dissolve in oil, not water) to where the body can actually pick them up, and add them into the bloodstream. In short, their argument is that there is a huge opportunity to take the primary constituent of a cheese-making waste product and use it to make many medicines work better.


    1. Poonia, A. Chapter 6: Potential of Milk Proteins as Nanoencapsulation Materials in Food Industry. In Ranjan S., Dasgupta N. & Lichtfouse E. (Eds) Nanoscience in Food and Agriculture 5, 2017, Springer International Publishing AG, Cham, Switzerland.

    2. Phadungath, C. 2005. Casein Micelle Structure: a Concise Review. Songklanakarin J. Sci. Technol. 27(1): 201-212.

    3. Liang J., Yan H., Yang H-J., Kim H. W., Wan X., Lee X., & Ko S. 2016. Synthesis and Controlled-release Properties of Chitosan/β-Lactoglobulin Nanoparticles as Carriers for Oral Administration of Epigallocatechin Gallate. Food Sci. Biotechnol. 25(6):1583-1590.

    4. Sato V. H. & Sato H. 2015. Enhancing Effect of β-Lactoglobulin on the Rate of Cyclosporin Absorption. Int. J. Drug Del. 7:191-196.