Bioconjugate Chemistry
Article
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CONCLUSION
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In the present study, we reported a novel strategy to construct
acid-sensitive micelles by directly conjugating the hydrophilic
PEG with a hydrophobic stearic acid derivative (C18) using an
acid-sensitive hydrazone bond. Furthermore, the anticancer
drug gemcitabine was conjugated with stearic acid (C18) to
produce the lipophilic prodrug, namely, GemC18, which was
then incorporated into the micelles. Acid-sensitive release was
observed when the micelles were incubated in slightly acidic
conditions, while the control PAC micelles were stable at the
same incubation conditions. Cellular-level acid sensitivity was
confirmed using a FRET technique. Lysosomal delivery of
GemC18 by micelles was found to be critical for the
cytotoxicity of the GemC18 because it was necessary for the
GemC18 to be hydrolyzed by lysosomal enzymes to generate
the active parent drug of gemcitabine. Most importantly,
GemC18 carried by the pH-sensitive PHC micelles showed a
significantly stronger in vivo antitumor activity than gemcitabine
HCl in solution, GemC18 in solution, and GemC18 in the pH-
insensitive PAC micelles, suggesting the acid-sensitive micelles
as an effective delivery system for the lipophilized gemcitabine
amide derivative, GemC18, and possibly the amide derivatives
of other anticancer drugs.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(14) Boudier, A., Aubert-Pouessel, A., Louis-Plence, P., Ger
́
ardin, C.,
̈
1H NMR and MS spectra of octadecanal; 1H NMR and MALDI
Jorgensen, C., Devoisselle, J. M., and Beg
́
u, S. (2009) The control of
1
MS spectra of PEG2000-hydrazide; H NMR and MALDI MS
dendritic cell maturation by pH-sensitive polyion complex micelles.
spectra of PEG2000-amine. This material is available free of
Biomaterials 30, 233−241.
(15) Gillies, E. R., Jonsson, T. B., and Frechet, J. M. (2004) Stimuli-
́
responsive supramolecular assemblies of linear-dendritic copolymers. J.
Am. Chem. Soc. 126, 11936−11943.
AUTHOR INFORMATION
■
(16) Toncheva, V., Schacht, E., Ng, S. Y., Barr, J., and Heller, J.
(2003) Use of block copolymers of poly(ortho esters) and poly
(ethylene glycol) micellar carriers as potential tumour targeting
systems. J. Drug Targeting 11, 345−353.
Corresponding Author
*Tel.: +1 512 495 4758; fax: +1 512 471 7474. E-mail address:
(17) Barton-Burke, M. (1999) Gemcitabine: a pharmacologic and
clinical overview. Cancer Nurs. 22, 176−183.
Notes
The authors declare no competing financial interest.
(18) Schmittel, A., Schuster, R., Bechrakis, N. E., Siehl, J. M.,
Foerster, M. H., Thiel, E., and Keilholz, U. (2005) A two-cohort phase
II clinical trial of gemcitabine plus treosulfan in patients with
metastatic uveal melanoma. Melanoma Res. 15, 447−451.
(19) Corrie, P. G., Shaw, J., Spanswick, V. J., Sehmbi, R., Jonson, A.,
Mayer, A., Bulusu, R., Hartley, J. A., and Cree, I. A. (2005) Phase I trial
combining gemcitabine and treosulfan in advanced cutaneous and
uveal melanoma patients. Br. J. Cancer 92, 1997−2003.
ACKNOWLEDGMENTS
■
This work was supported in part by a National Cancer Institute
grant CA135274 (to Z.C.). We would like to thank Dr. Yue Li
at the Microscopy Core Facility at the Dell Pediatric Research
Institute at The University of Texas at Austin for assistance in
acquiring the confocal microscopic images. The Fluorolog3
Fluorimeter was funded by the National Science Foundation
Grant CHE-094750.
(20) Brusa, P., Immordino, M. L., Rocco, F., and Cattel, L. (2007)
Antitumor activity and pharmacokinetics of liposomes containing
lipophilic gemcitabine prodrugs. Anticancer Res. 27, 195−199.
(21) Immordino, M. L., Brusa, P., Rocco, F., Arpicco, S., Ceruti, M.,
and Cattel, L. (2004) Preparation, characterization, cytotoxicity and
pharmacokinetics of liposomes containing lipophilic gemcitabine
prodrugs. J. Controlled Release 100, 331−346.
(22) Celano, M., Calvagno, M. G., Bulotta, S., Paolino, D., Arturi, F.,
Rotiroti, D., Filetti, S., Fresta, M., and Russo, D. (2004) Cytotoxic
effects of gemcitabine-loaded liposomes in human anaplastic thyroid
carcinoma cells. BMC Cancer 4, 63.
(23) Sloat, B. R., Sandoval, M. A., Li, D., Chung, W. G., Lansakara-P,
D. S., Proteau, P. J., Kiguchi, K., DiGiovanni, J., and Cui, Z. (2011) In
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(24) Reddy, L. H., Dubernet, C., Mouelhi, S. L., Marque, P. E.,
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