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Phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery

The hydrophobicity and high potency of many therapeutic agents makes them difficult to use effectively in clinical practice. This work focuses on conjugating phospholipid tails (2T) onto podophyllotoxin (P) and its analogue (N) using a linker and characterizing the effects of their incorporation int...

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Autores principales: Márquez, Mendi G., Dotson, Rachel, Pias, Sally, Frolova, Liliya V., Tartis, Michaelann S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940203/
https://www.ncbi.nlm.nih.gov/pubmed/31911893
http://dx.doi.org/10.7150/ntno.37738
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author Márquez, Mendi G.
Dotson, Rachel
Pias, Sally
Frolova, Liliya V.
Tartis, Michaelann S.
author_facet Márquez, Mendi G.
Dotson, Rachel
Pias, Sally
Frolova, Liliya V.
Tartis, Michaelann S.
author_sort Márquez, Mendi G.
collection PubMed
description The hydrophobicity and high potency of many therapeutic agents makes them difficult to use effectively in clinical practice. This work focuses on conjugating phospholipid tails (2T) onto podophyllotoxin (P) and its analogue (N) using a linker and characterizing the effects of their incorporation into lipid-based drug delivery vehicles for triggered ultrasound delivery. Differential Scanning Calorimetry results show that successfully synthesized lipophilic prodrugs, 2T-P (~28 % yield) and 2T-N(~26 % yield), incorporate within the lipid membranes of liposomes. As a result of this, increased stability and incorporation are observed in 2T-P and 2T-N in comparison to the parent compounds P and N. Molecular dynamic simulation results support that prodrugs remain within the lipid membrane over a relevant range of concentrations. 2T-N's (IC(50): 20 nM) biological activity was retained in HeLa cells (cervical cancer), whereas 2T-P's (IC(50): ~4 µM) suffered, presumably due to steric hindrance. Proof-of-concept studies using ultrasound in vitro microbubble and nanodroplet delivery vehicles establish that these prodrugs are capable of localized drug delivery. This study provides useful information about the synthesis of double tail analogues of insoluble chemotherapeutic agents to facilitate incorporation into drug delivery vehicles. The phospholipid attachment strategy presented here could be applied to other well suited drugs such as gemcitabine, commonly known for its treatment of pancreatic cancer.
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spelling pubmed-69402032020-01-07 Phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery Márquez, Mendi G. Dotson, Rachel Pias, Sally Frolova, Liliya V. Tartis, Michaelann S. Nanotheranostics Research Paper The hydrophobicity and high potency of many therapeutic agents makes them difficult to use effectively in clinical practice. This work focuses on conjugating phospholipid tails (2T) onto podophyllotoxin (P) and its analogue (N) using a linker and characterizing the effects of their incorporation into lipid-based drug delivery vehicles for triggered ultrasound delivery. Differential Scanning Calorimetry results show that successfully synthesized lipophilic prodrugs, 2T-P (~28 % yield) and 2T-N(~26 % yield), incorporate within the lipid membranes of liposomes. As a result of this, increased stability and incorporation are observed in 2T-P and 2T-N in comparison to the parent compounds P and N. Molecular dynamic simulation results support that prodrugs remain within the lipid membrane over a relevant range of concentrations. 2T-N's (IC(50): 20 nM) biological activity was retained in HeLa cells (cervical cancer), whereas 2T-P's (IC(50): ~4 µM) suffered, presumably due to steric hindrance. Proof-of-concept studies using ultrasound in vitro microbubble and nanodroplet delivery vehicles establish that these prodrugs are capable of localized drug delivery. This study provides useful information about the synthesis of double tail analogues of insoluble chemotherapeutic agents to facilitate incorporation into drug delivery vehicles. The phospholipid attachment strategy presented here could be applied to other well suited drugs such as gemcitabine, commonly known for its treatment of pancreatic cancer. Ivyspring International Publisher 2020-01-01 /pmc/articles/PMC6940203/ /pubmed/31911893 http://dx.doi.org/10.7150/ntno.37738 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Márquez, Mendi G.
Dotson, Rachel
Pias, Sally
Frolova, Liliya V.
Tartis, Michaelann S.
Phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery
title Phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery
title_full Phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery
title_fullStr Phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery
title_full_unstemmed Phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery
title_short Phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery
title_sort phospholipid prodrug conjugates of insoluble chemotherapeutic agents for ultrasound targeted drug delivery
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940203/
https://www.ncbi.nlm.nih.gov/pubmed/31911893
http://dx.doi.org/10.7150/ntno.37738
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