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.
Highlights
As cancer is a leading cause of death worldwide, there is a high effort to find new therapies
All other cell lines had distinctly higher IC50 ranging from 15 to 35 nmol/L. It was tested whether the differences in in vitro sensitivity to doxorubicin can be reproduced in vivo in derived xenograft tumors
The cell line 1411HP represents a model of natural drug resistance as these cells were derived from a tumor of a patient with refractory disease after chemotherapy [19, 20], whereas the acquired drug resistance of A2780cis was artificially established derived from the cell line A2780 [21]
Summary
As cancer is a leading cause of death worldwide, there is a high effort to find new therapies. There is already a multitude of antineoplastic agents, the success of chemotherapy is often limited. Major obstacles in cancer therapy are dose-limiting systemic toxicities, due to nonspecific drug delivery and chemotherapy resistance [1,2,3,4]. Achieving higher intratumoral drug concentrations while protecting normal tissue would improve therapy outcome and diminish severe side effects. The increasing importance of resistant tumors is a huge challenge which has to be tackled. The enhanced permeability and retention (EPR) effect, discovered by Matsumara and Maeda [5, 6], is well
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