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Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance
AK. Heinrich, H. Lucas, L. Schindler, P. Chytil, T. Etrych, K. Mäder, T. Mueller,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
NLK
Free Medical Journals
od 2001 do Před 1 rokem
Open Access Digital Library
od 2001-11-01
Open Access Digital Library
od 2001-11-01
- MeSH
- chemorezistence * MeSH
- koncentrace vodíkových iontů * MeSH
- lékové transportní systémy * MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků * MeSH
- polymery * MeSH
- protinádorové látky aplikace a dávkování MeSH
- uvolňování léčiv * MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR.
Institute of Macromolecular Chemistry AS CR Prague Czech Republic
Institute of Pharmacy Martin Luther University Halle Wittenberg Halle Germany
Citace poskytuje Crossref.org
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