title: Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.
abstract: 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.
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Heinrich
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Lucas
authors.affiliation: Institute of Macromolecular Chemistry AS CR, Prague, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Schindler
authors.affiliation: Institute of Macromolecular Chemistry AS CR, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Chytil
authors.affiliation: Institute of Macromolecular Chemistry AS CR, Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Mäder
authors.affiliation: Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. thomas.mueller@medizin.uni-halle.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016503:Drug Delivery Systems; D065546:Drug Liberation; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D011108:Polymers; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011108:Polymers