Dataset Information

Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs.

ABSTRACT: Cellular uptake is limiting for the efficacy of many cytotoxic drugs used to treat cancer. Identifying endocytic mechanisms that can be modulated with targeted, clinically-relevant interventions is important to enhance the efficacy of various cancer drugs. We identify that flotillin-dependent endocytosis can be targeted and upregulated by ultrasound and microbubble (USMB) treatments to enhance uptake and efficacy of cancer drugs such as cisplatin. USMB involves targeted ultrasound following administration of encapsulated microbubbles, used clinically for enhanced ultrasound image contrast. USMB treatments robustly enhanced internalization of the molecular scaffold protein flotillin, as well as flotillin-dependent fluid-phase internalization, a phenomenon dependent on the protein palmitoyltransferase DHHC5 and the Src-family kinase Fyn. USMB treatment enhanced DNA damage and cell killing elicited by the cytotoxic agent cisplatin in a flotillin-dependent manner. Thus, flotillin-dependent endocytosis can be modulated by clinically-relevant USMB treatments to enhance drug uptake and efficacy, revealing an important new strategy for targeted drug delivery for cancer treatment.

SUBMITTER: Fekri F

PROVIDER: S-EPMC6882852 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs.

Fekri Farnaz F Abousawan John J Bautista Stephen S Orofiamma Laura L Dayam Roya M RM Antonescu Costin N CN Karshafian Raffi R

Scientific reports 20191128 1

Cellular uptake is limiting for the efficacy of many cytotoxic drugs used to treat cancer. Identifying endocytic mechanisms that can be modulated with targeted, clinically-relevant interventions is important to enhance the efficacy of various cancer drugs. We identify that flotillin-dependent endocytosis can be targeted and upregulated by ultrasound and microbubble (USMB) treatments to enhance uptake and efficacy of cancer drugs such as cisplatin. USMB involves targeted ultrasound following admi ...[more]

PMID: 31780775

Similar Datasets

Project description:The lack of knowledge about the uptake of NPs by biological cells poses a significant problem for drug delivery. For this reason, designing an appropriate model is the main challenge for modelers. To address this problem, molecular modeling studies that can describe the mechanism of cellular uptake of drug-loaded nanoparticles have been conducted in recent decades. In this context, we developed three different models for the amphipathic nature of drug-loaded nanoparticles (MTX-SS-γ-PGA), whose cellular uptake mechanism was predicted by molecular dynamics studies. Many factors affect nanoparticle uptake, including nanoparticle physicochemical properties, protein-particle interactions, and subsequent agglomeration, diffusion, and sedimentation. Therefore, the scientific community needs to understand how these factors can be controlled and the NP uptake of nanoparticles. Based on these considerations, in this study, we investigated for the first time the effects of the selected physicochemical properties of the anticancer drug methotrexate (MTX) grafted with hydrophilic-γ-polyglutamic acid (MTX-SS-γ-PGA) on its cellular uptake at different pH values. To answer this question, we developed three theoretical models describing drug-loaded nanoparticles (MTX-SS-γ-PGA) at three different pH values, such as (1) pH 7.0 (the so-called neutral pH model), (2) pH 6.4 (the so-called tumor pH model), and (3) pH 2.0 (the so-called stomach pH model). Exceptionally, the electron density profile shows that the tumor model interacts more strongly with the head groups of the lipid bilayer than the other models due to charge fluctuations. Hydrogen bonding and RDF analyses provide information about the solution of the NPs with water and their interaction with the lipid bilayer. Finally, dipole moment and HOMO-LUMO analysis showed the free energy of the solution in the water phase and chemical reactivity, which are particularly useful for determining the cellular uptake of the NPs. The proposed study provides fundamental insights into molecular dynamics (MD) that will allow researchers to determine the influence of pH, structure, charge, and energetics of NPs on the cellular uptake of anticancer drugs. We believe that our current study will be useful in developing a new model for drug delivery to cancer cells with a much more efficient and less time-consuming model.

Dataset Information

Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs.

Publications

Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets