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Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect

Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect
Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect

The chemotherapeutic gemcitabine was actively and stably loaded into lipid nanoparticles through the formation of a prodrug. Gemcitabine was chemically modified to increase the lipophilicity and introduce a weak base moiety for remote loading. Several derivatives were synthesized and screened for their potential to be good liposomal drug candidates for remote loading by studying their solubility, stability, cytotoxicity, and loading efficiency. Two morpholino derivatives of GEM (22 and 23) were chosen as the preferred prodrugs for this purpose as they possessed the best loading efficiencies (100% for drug-to-lipid ratio of 0.36 w/w). This is a considerable improvement over a passive loading strategy where typical loading efficiencies are on the order of ∼10-20% for a drug-to-lipid ratio of ∼0.01. Liposomes loaded with these two prodrugs were studied in an s.c. tumor model in vivo and showed improved therapeutic effect over free GEM (∼2-fold) and saline control (8- to 10-fold). This work demonstrates how chemical modification of a known hydrophilic drug can lead to improved loading, stability, and drug delivery in vivo.

1043-1802
226-237
May, Jonathan P.
b54a262b-9f32-4435-8866-3b9c495294f3
Undzys, Elijus
226e7879-8bef-4715-9e72-d405e59d6dcb
Roy, Aniruddha
173c3ff0-7e0e-4633-926a-30e1a9c0578a
Li, Shyh Dar
9a960896-36e7-4eb8-bd39-55580c60e36d
May, Jonathan P.
b54a262b-9f32-4435-8866-3b9c495294f3
Undzys, Elijus
226e7879-8bef-4715-9e72-d405e59d6dcb
Roy, Aniruddha
173c3ff0-7e0e-4633-926a-30e1a9c0578a
Li, Shyh Dar
9a960896-36e7-4eb8-bd39-55580c60e36d

May, Jonathan P., Undzys, Elijus, Roy, Aniruddha and Li, Shyh Dar (2016) Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect. Bioconjugate Chemistry, 27 (1), 226-237. (doi:10.1021/acs.bioconjchem.5b00619).

Record type: Article

Abstract

The chemotherapeutic gemcitabine was actively and stably loaded into lipid nanoparticles through the formation of a prodrug. Gemcitabine was chemically modified to increase the lipophilicity and introduce a weak base moiety for remote loading. Several derivatives were synthesized and screened for their potential to be good liposomal drug candidates for remote loading by studying their solubility, stability, cytotoxicity, and loading efficiency. Two morpholino derivatives of GEM (22 and 23) were chosen as the preferred prodrugs for this purpose as they possessed the best loading efficiencies (100% for drug-to-lipid ratio of 0.36 w/w). This is a considerable improvement over a passive loading strategy where typical loading efficiencies are on the order of ∼10-20% for a drug-to-lipid ratio of ∼0.01. Liposomes loaded with these two prodrugs were studied in an s.c. tumor model in vivo and showed improved therapeutic effect over free GEM (∼2-fold) and saline control (8- to 10-fold). This work demonstrates how chemical modification of a known hydrophilic drug can lead to improved loading, stability, and drug delivery in vivo.

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Published date: 20 January 2016

Identifiers

Local EPrints ID: 455410
URI: http://eprints.soton.ac.uk/id/eprint/455410
ISSN: 1043-1802
PURE UUID: 6cdd4d43-c12b-4f25-bace-c07a5dceeac1
ORCID for Jonathan P. May: ORCID iD orcid.org/0000-0003-1651-130X

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Date deposited: 21 Mar 2022 17:41
Last modified: 22 Mar 2022 02:55

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Contributors

Author: Jonathan P. May ORCID iD
Author: Elijus Undzys
Author: Aniruddha Roy
Author: Shyh Dar Li

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