Improved tumor-specific drug accumulation by polymer therapeutics with pH-sensitive drug release overcomes chemotherapy resistance

0460441 - ÚMCH 2017 RIV US eng J - Článek v odborném periodiku
Heinrich, A. K. - Lucas, H. - Schindler, Lucie - Chytil, Petr - Etrych, Tomáš - Mäder, K. - Mueller, T.
Improved tumor-specific drug accumulation by polymer therapeutics with pH-sensitive drug release overcomes chemotherapy resistance.
Molecular Cancer Therapeutics. Roč. 15, č. 5 (2016), s. 998-1007. ISSN 1535-7163. E-ISSN 1538-8514
Grant CEP: GA MŠMT(CZ) ED1.1.00/02.0109; GA ČR(CZ) GA15-02986S; GA ČR(CZ) GCP207/12/J030; GA ČR(CZ) GA14-12742S
Institucionální podpora: RVO:61389013
Klíčová slova: HPMA copolymers * doxorubicin * pH-sensitivity
Kód oboru RIV: CD - Makromolekulární chemie
Impakt faktor: 5.764, rok: 2016

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.
Trvalý link: http://hdl.handle.net/11104/0260566