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Magnetic-Fe/Fe(3)O(4)-nanoparticle-bound SN38 as carboxylesterase-cleavable prodrug for the delivery to tumors within monocytes/macrophages.

ABSTRACT: The targeted delivery of therapeutics to the tumor site is highly desirable in cancer treatment, because it is capable of minimizing collateral damage. Herein, we report the synthesis of a nanoplatform, which is composed of a 15 ± 1 nm diameter core/shell Fe/Fe(3)O(4) magnetic nanoparticles (MNPs) and the topoisomerase I blocker SN38 bound to the surface of the MNPs via a carboxylesterase cleavable linker. This nanoplatform demonstrated high heating ability (SAR = 522 ± 40 W/g) in an AC-magnetic field. For the purpose of targeted delivery, this nanoplatform was loaded into tumor-homing double-stable RAW264.7 cells (mouse monocyte/macrophage-like cells (Mo/Ma)), which have been engineered to express intracellular carboxylesterase (InCE) upon addition of doxycycline by a Tet-On Advanced system. The nanoplatform was taken up efficiently by these tumor-homing cells. They showed low toxicity even at high nanoplatform concentration. SN38 was released successfully by switching on the Tet-On Advanced system. We have demonstrated that this nanoplatform can be potentially used for thermochemotherapy. We will be able to achieve the following goals: (1) Specifically deliver the SN38 prodrug and magnetic nanoparticles to the cancer site as the payload of tumor-homing double-stable RAW264.7 cells; (2) Release of chemotherapeutic SN38 at the cancer site by means of the self-containing Tet-On Advanced system; (3) Provide localized magnetic hyperthermia to enhance the cancer treatment, both by killing cancer cells through magnetic heating and by activating the immune system.

SUBMITTER: Wang H

PROVIDER: S-EPMC3388369 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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Magnetic-Fe/Fe(3)O(4)-nanoparticle-bound SN38 as carboxylesterase-cleavable prodrug for the delivery to tumors within monocytes/macrophages.

Wang Hongwang H Shrestha Tej B TB Basel Matthew T MT Dani Raj Kumar RK Seo Gwi-Moon GM Balivada Sivasai S Pyle Marla M MM Prock Heidy H Koper Olga B OB Thapa Prem S PS Moore David D Li Ping P Chikan Viktor V Troyer Deryl L DL Bossmann Stefan H SH

Beilstein journal of nanotechnology 20120613

The targeted delivery of therapeutics to the tumor site is highly desirable in cancer treatment, because it is capable of minimizing collateral damage. Herein, we report the synthesis of a nanoplatform, which is composed of a 15 ± 1 nm diameter core/shell Fe/Fe(3)O(4) magnetic nanoparticles (MNPs) and the topoisomerase I blocker SN38 bound to the surface of the MNPs via a carboxylesterase cleavable linker. This nanoplatform demonstrated high heating ability (SAR = 522 ± 40 W/g) in an AC-magnetic ...[more]

PMID: 23016149

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Project description:Two major isoforms of human carboxylesterases (CEs) are found in metabolically active tissues, CES1 and CES2. These hydrolytic enzymes are involved in xenobiotic and endobiotic metabolism. CES1 is abundantly expressed in human liver and monocytes/macrophages, including the THP1 cell line; CES2 is expressed in liver but not in monocytes/macrophages. The cholesteryl ester hydrolysis activity in human macrophages has been attributed to CES1. Here, we report the direct inhibitory effects of several endogenous oxysterols and fatty acids on the CE activity of THP1 monocytes/macrophages and recombinant human CES1 and CES2. Using THP1 whole-cell lysates we found: (1) 27-hydroxycholesterol (27-HC) is a potent inhibitor of carboxylesterase activity (IC50=33 nM); (2) 24(S),25-epoxycholesterol had moderate inhibitory activity (IC(50)=8.1 microM); and (3) cholesterol, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 25-hydroxycholesterol each had little inhibitory activity. 27-HC was a partially noncompetitive inhibitor of recombinant CES1 (K(iapp)=10 nM) and impaired intracellular CES1 activity following treatment of intact THP1 cells. In contrast, recombinant CES2 activity was not inhibited by 27-HC, suggesting isoform-selective inhibition by 27-HC. Furthermore, unsaturated fatty acids were better inhibitors of CES1 activity than saturated fatty acids, while CES2 activity was unaffected by any fatty acid. Arachidonic acid (AA) was the most potent fatty acid inhibitor of recombinant CES1 and acted by a noncompetitive mechanism (K(iapp)=1.7 microM); when not complexed to albumin, exogenous AA penetrated intact THP1 cells and inhibited CES1. Inhibition results are discussed in light of recent structural models for CES1 that describe ligand binding sites separate from the active site. In addition, oxysterol-mediated inhibition of CES1 activity was demonstrated by pretreatment of human liver homogenates or intact THP1 cells with exogenous 27-HC, which resulted in significantly reduced hydrolysis of the pyrethroid insecticide bioresmethrin, a CES1-specific xenobiotic substrate. Collectively, these findings suggest that CE activity of recombinant CES1, cell lysates, and intact cells can be impaired by naturally occurring lipids, which may compromise the ability of CES1 to both detoxify environmental pollutants and metabolize endogenous compounds in vivo.

Project description:Cathepsin B is a lysosomal cysteine protease that plays an important role in cancer, atherosclerosis, and other inflammatory diseases. The suppression of cathepsin B can inhibit tumor growth. The overexpression of cathepsin B can be used for the imaging and photodynamic therapy (PDT) of cancer. PDT targeting of cathepsin B may have a significant potential for selective destruction of cells with high cathepsin B activity. We synthesized a cathepsin B-cleavable polymeric photosensitizer prodrug (CTSB-PPP) that releases pheophorbide a (Pha), an efficient photosensitizer upon activation with cathepsin B. We determined the concentration dependant uptake in vitro, the safety, and subsequent PDT-induced toxicity of CTSB-PPP, and ROS production. CTSB-PPP was cleaved in bone marrow cells (BMCs), which express a high cathepsin B level. We showed that the intracellular fluorescence of Pha increased with increasing doses (3-48 µM) and exerted significant dark toxicity above 12 µM, as assessed by MTT assay. However, 6 µM showed no toxicity on cell viability and ex vivo vascular function. Time-dependent studies revealed that cellular accumulation of CTSB-PPP (6 µM) peaked at 60 min of treatment. PDT (light dose: 0-100 J/cm2, fluence rate: 100 mW/cm2) was applied after CTSB-PPP treatment (6 µM for 60 min) using a special frontal light diffuser coupled to a diode laser (671 nm). PDT resulted in a light dose-dependent reduction in the viability of BMCs and was associated with an increased intracellular ROS generation. Fluorescence and ROS generation was significantly reduced when the BMCs were pre-treated with E64-d, a cysteine protease inhibitor. In conclusion, we provide evidence that CTSB-PPP showed no dark toxicity at low concentrations. This probe could be utilized as a potential imaging agent to identify cells or tissues with cathepsin B activity. CTSB-PPP-based PDT results in effective cytotoxicity and thus, holds great promise as a therapeutic agent for achieving the selective destruction of cells with high cathepsin B activity.

Dataset Information

Magnetic-Fe/Fe(3)O(4)-nanoparticle-bound SN38 as carboxylesterase-cleavable prodrug for the delivery to tumors within monocytes/macrophages.

Publications

Magnetic-Fe/Fe(3)O(4)-nanoparticle-bound SN38 as carboxylesterase-cleavable prodrug for the delivery to tumors within monocytes/macrophages.

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