Abstract
Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. Cancer Res; 77(21); 6021-32. ©2017 AACR.
Highlights
Despite being one of the most widely used treatment strategies for cancer, the efficacy of chemotherapy is undermined by drug resistance and postchemotherapy tumor relapse, as well as serious side effects due to the systemic distribution and limited tumor cytotoxicity of drugs [1, 2]
The accumulation of 125I-HSA was markedly higher in macrophage-transferred tumors than in PBS-treated tumors (Fig. 3E). These results indicated that macrophage transfer increased tumor microvascular permeability, which might have been attributed to inflammation induced by macrophages or cytokines, such as VEGF released by macrophages in the tumor microenvironment [27], and thereby enhancing tumor accumulation of GO(HPPH)-polyethylene glycol (PEG)
We investigated whether macrophage recruitment to tumors could affect the Photodynamic therapy (PDT) effect of GO(HPPH)-PEG
Summary
Despite being one of the most widely used treatment strategies for cancer, the efficacy of chemotherapy is undermined by drug resistance and postchemotherapy tumor relapse, as well as serious side effects due to the systemic distribution and limited tumor cytotoxicity of drugs [1, 2]. Photodynamic therapy (PDT), which is based on the delivery of photosensitizers, followed by light irradiation at a wavelength that can induce the generation of singlet oxygen or reactive oxygen species, is a safe treatment strategy that has been successfully used to treat cancer and other diseases [3, 4]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). An unresolved challenge is the efficient delivery of photosensitizers to the tumor site to enhance tumor response [8, 9].
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