TY - JOUR
T1 - Balanced lipase interactions for degradation-controlled paclitaxel release from lipid cubic phase formulations
AU - Dully, Michele
AU - Bhattacharya, Shayon
AU - Verma, Vivek
AU - Murray, David
AU - Thompson, Damien
AU - Soulimane, Tewfik
AU - Hudson, Sarah P.
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2022/2
Y1 - 2022/2
N2 - Lipid cubic phase (LCP) formulations enhance the intestinal solubility and bioavailability of hydrophobic drugs by reducing precipitation and facilitating their mass transport to the intestinal surface for absorption. LCPs with an ester linkage connecting the acyl chain to the glycerol backbone (monoacylglycerols), are susceptible to chemical digestion by several lipolytic enzymes including lipases, accelerating the release of hydrophobic agents from the lipid bilayers of the matrix. Unlike regular enzymes that transform soluble substrates, lipolytic enzymes act at the interface of water and insoluble lipid. Therefore, compounds that bind to this interface can enhance or inhibit the activity of enzymes to varying extent. Here, we explore how the lipolysis rate can be tuned by the interfacial interaction of porcine pancreatic lipase with monoolein LCPs containing a known lipase inhibitor, tetrahydrolipstatin. Release of the Biopharmaceutical Classification System (BCS) class IV drug, paclitaxel, from the inhibitor-modified LCP was examined in the presence of lipase and its effectors colipase and calcium. By combining experimental dynamic digestion studies, thermodynamic measurements and molecular dynamics simulations of the competitive inhibition of lipase by tetrahydrolipstatin, we reveal the role and mode of action of lipase effectors in creating a precisely-balanced degradation-controlled LCP release system for the poorly soluble paclitaxel drug.
AB - Lipid cubic phase (LCP) formulations enhance the intestinal solubility and bioavailability of hydrophobic drugs by reducing precipitation and facilitating their mass transport to the intestinal surface for absorption. LCPs with an ester linkage connecting the acyl chain to the glycerol backbone (monoacylglycerols), are susceptible to chemical digestion by several lipolytic enzymes including lipases, accelerating the release of hydrophobic agents from the lipid bilayers of the matrix. Unlike regular enzymes that transform soluble substrates, lipolytic enzymes act at the interface of water and insoluble lipid. Therefore, compounds that bind to this interface can enhance or inhibit the activity of enzymes to varying extent. Here, we explore how the lipolysis rate can be tuned by the interfacial interaction of porcine pancreatic lipase with monoolein LCPs containing a known lipase inhibitor, tetrahydrolipstatin. Release of the Biopharmaceutical Classification System (BCS) class IV drug, paclitaxel, from the inhibitor-modified LCP was examined in the presence of lipase and its effectors colipase and calcium. By combining experimental dynamic digestion studies, thermodynamic measurements and molecular dynamics simulations of the competitive inhibition of lipase by tetrahydrolipstatin, we reveal the role and mode of action of lipase effectors in creating a precisely-balanced degradation-controlled LCP release system for the poorly soluble paclitaxel drug.
KW - Binding energy
KW - Colipase
KW - Controlled release
KW - Density functional theory
KW - Lipid cubic phase
KW - Molecular dynamics
KW - Paclitaxel
KW - Pancreatic lipase
KW - Predictive modelling
KW - Tetrahydrolipstatin
UR - http://www.scopus.com/inward/record.url?scp=85115629464&partnerID=8YFLogxK
U2 - 10.1016/j.jcis.2021.09.024
DO - 10.1016/j.jcis.2021.09.024
M3 - Article
C2 - 34571316
AN - SCOPUS:85115629464
SN - 0021-9797
VL - 607
SP - 978
EP - 991
JO - Journal of Colloid and Interface Science
JF - Journal of Colloid and Interface Science
ER -