Abstract Gliomas are the most common primary brain tumors in adults. With the highly invasive growth pattern, gliomas often escape current therapeutic modalities including combinations of surgery, radiotherapy and chemotherapy. Recent studies implicate that a minority population of glioma stem cells (GSCs) are responsible for glioma maintenance and recurrence. Interleukin (IL)-1 beta, IL-6 and IL-8 are pleiotropic proinflammatory cytokines and their excessive production in the tumor microenvironment is associated with poor disease outcome in many cancer types, including glioma. These cytokines promote tumor growth via induction of proteins associated with tumor invasion and angiogenesis and anti-apoptosis. We hypothesize that GSCs acquire their chemo-resistance and invasion by excessive cytokine production. To test the hypothesis, we compared the cytokine gene expression of a human GSC-enriched population in serum-free medium (SFM) in the presence of epidermal growth factor and fibroblast growth factor, to that of glioma cells in serum-containing medium (SCM). SFM is the neural stem/progenitor cell (NPC) medium in which NPCs proliferate in neurospheres and this medium also has been used to enrich GSCs. We found that IL-1 beta and IL-6 were upregulated in GSC-enriched population along with increased expression of Nestin, a marker of neural stem cells. More interestingly, Smad interacting protein 1 (SIP1), which is thought to be involved in glioma cell migration and invasion, was also increased in the GSC-enriched population. The paralleled upregulation of IL-1 beta and IL-6 with Nestin and SIP1 in GSC-enriched population suggest that there is a possible correlation between them. The correlation is now under investigation. Since IL-1 beta is elevated in GSC enriched population, we further determined whether IL-1 beta plays a critical role in glioma growth. Glioma cells were co-cultured with mouse NPCs expressing IL-1 receptor antagonist (IL-1ra), which can bind to IL-1 receptors without transmitting activation signals and represents a competitive inhibitor of IL-1. Proliferation of glioma cells, which were modified to express Renilla luciferase, was measured using bioluminescence imaging. Our results showed that proliferation of glioma cells was inhibited in the co-culture with NPCs expressing IL-1ra, but not in the co-culture with NPCs without expression of IL-1ra, compared to glioma cells cultured alone. The results suggest that IL-1 has an important role in glioma cell growth and NPCs engineered to express IL-1ra have therapeutic potential for gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3336.
Enzyme-activated prodrugs have been investigated and sought after as highly specific, low-side-effect treatments, especially for cancer therapy. Unfortunately, excellent targets for enzyme-activated therapy are rare. Here a system based on cell delivery that can carry both a prodrug and an activating enzyme to the cancer site is demonstrated. Raw264.7 cells (mouse monocyte/macrophage-like cells, Mo/Ma) are engineered to express intracellular rabbit carboxylesterase (InCE), which is a potent activator of the prodrug irinotecan to SN38. InCE expression is regulated by the TetOn® system, which silences the gene unless a tetracycline, such as doxycycline, is present. Concurrently, an irinotecan-like prodrug, which is conjugated to dextran and can be loaded into the cytoplasm of Mo/Ma, is synthesized. To test the system, a murine pancreatic cancer model is generated by intraperitoneal (i.p.) injection of Pan02 cells. Engineered Mo/Ma are loaded with the prodrug and are injected i.p. Two days later, doxycycline was given i.p. to activate InCE, which activated the prodrug. A survival study demonstrates that this system significantly increased survival in a murine pancreatic cancer model. Thus, for the first time, a prodrug/activating enzyme system, which is self-contained within tumor-homing cells and can prolong the life of i.p. pancreatic tumor bearing mice, is demonstrated.
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.
Localized magnetic hyperthermia as a treatment modality for cancer has generated renewed interest, particularly if it can be targeted to the tumor site. We examined whether tumor-tropic neural progenitor cells (NPCs) could be utilized as cell delivery vehicles for achieving preferential accumulation of core/shell iron/iron oxide magnetic nanoparticles (MNPs) within a mouse model of melanoma. We developed aminosiloxane-porphyrin functionalized MNPs, evaluated cell viability and loading efficiency, and transplanted neural progenitor cells loaded with this cargo into mice with melanoma. NPCs were efficiently loaded with core/shell Fe/Fe(3)O(4) MNPs with minimal cytotoxicity; the MNPs accumulated as aggregates in the cytosol. The NPCs loaded with MNPs could travel to subcutaneous melanomas, and after A/C (alternating current) magnetic field (AMF) exposure, the targeted delivery of MNPs by the cells resulted in a measurable regression of the tumors. The tumor attenuation was significant (p < 0.05) a short time (24 h) after the last of three AMF exposures.
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