Nanoformulation of Geranylgeranyltransferase-I Inhibitors for Cancer Therapy: Liposomal Encapsulation and pH-Dependent Delivery to Cancer Cells

PloS One
Jie LuF Tamanoi

Abstract

Small molecule inhibitors against protein geranylgeranyltransferase-I such as P61A6 have been shown to inhibit proliferation of a variety of human cancer cells and exhibit antitumor activity in mouse models. Development of these inhibitors could be dramatically accelerated by conferring tumor targeting and controlled release capability. As a first step towards this goal, we have encapsulated P61A6 into a new type of liposomes that open and release cargos only under low pH condition. These low pH-release type liposomes were prepared by adjusting the ratio of two types of phospholipid derivatives. Loading of geranylgeranyltransferase-I inhibitor (GGTI) generated liposomes with average diameter of 50-100 nm. GGTI release in solution was sharply dependent on pH values, only showing release at pH lower than 6. Release of cargos in a pH-dependent manner inside the cell was demonstrated by the use of a proton pump inhibitor Bafilomycin A1 that Increased lysosomal pH and inhibited the release of a dye carried in the pH-liposome. Delivery of GGTI to human pancreatic cancer cells was demonstrated by the inhibition of protein geranylgeranylation inside the cell and this effect was blocked by Bafilomycin A1. In addition, GGTI delivered by ...Continue Reading

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Citations

Mar 1, 2019·Science and Technology of Advanced Materials·Lei LiGang Liu
Nov 4, 2017·Cancer Research·Axel SchambachMichael A Morgan
Jul 9, 2021·Journal of Medicinal Chemistry·Edyta Gendaszewska-DarmachKatarzyna M Błażewska

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Methods Mentioned

BETA
geranylgeranylation
xenografts
FCS
fluorescence microscopy
electrophoresis
Fluorescent
Dynamic light scattering
Fluorescent microscopy
FACS
Flow cytometry

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