Beta-casein micellar nanocarriers for oral drug delivery

β-casein is a 24 kDa protein that self-organizes into well-defined core-shell micelles. We developed these micelles as efficient nanocarriers for oral delivery of a range of poorly soluble pharmaceutical agents [1], showing that we achieve superior properties over common conventional polymeric micelles. We will present work with celecoxib, an anti-inflammatory hydrophobic NSAID drug utilized for the treatment of rheumatoid arthritis and osteoarthritis, also evaluated as a potent anticancer drug. We demonstrate very high encapsulation loads, the ability to lyophilize the formulation without a cryoprotectant, long-term physical and chemical stability of the powder, and fully reversible reconstitution and preservation of the spherical morphology [2]. Further, analysis in both bulk solution and in dry form indicates strong drug-protein interactions that lead to encapsulation in a non-crystalline drug conformation [3]. This in turn leads to improved drug solubility in intestinal fluids upon drug release and an increase in the bioavailability of our formulation compared to the commercial drug Celebra®, as indicated in crossover pharmacokinetic studies in pigs [4]. The versatility of our platform will further be illustrated by recent work of co-encapsulating clinically relevant antiretroviral (ARV) fixed-dose combinations [5].

References:

[1] Danino D, Barenholz Y. Nanoencapsulation of Drugs and Therapeutic Bioactive Agents in b-Casein Assemblies for Oral Delivery. US patent 08871276, US patent 08865223.

[2] Bachar M, Mandelbaum A, Portnaya I, Barenholz Y and Danino D. A Novel Oral Drug Nanocarrier Based on Self-Assembled -casein Micelles. J Control Release 160, 164-171 (2012).

[3] Turovsky T, Khalfin R, Kababya S, Schmidt A, Barenholz Y and Danino D. Celecoxib Encapsulation in β-casein Micelles: Structure, Interactions, and Conformation. Langmuir 31(26), 7183-7192 (2015).

[4] Perlstein H, Felsan Y, Turovsky T, Rubinstein A, Danino D, Stepensky D and Barenholz Y. Beta-Casein Nanocarriers of Celecoxib for Improved Gastrointestinal Bioavailability. Eur J Nanomedicine 6(4), 217-226 (2014).

[5] Chauhan SP, Ionita I, Halamish HM, Sosnik A and Danino D. Multidomain drug delivery systems of β-casein micelles for the local oral co-administration of antiretroviral combinations. J Colloid Interf Sci, 592, 156-166 (2021).