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1.  Human Xenografts Are Not Rejected in a Naturally Occurring Immunodeficient Porcine Line: A Human Tumor Model in Pigs 
BioResearch Open Access  2012;1(2):63-68.
Abstract
Animal models for cancer therapy are invaluable for preclinical testing of potential cancer treatments; however, therapies tested in such models often fail to translate into clinical settings. Therefore, a better preclinical model for cancer treatment testing is needed. Here we demonstrate that an immunodeficient line of pigs can host and support the growth of xenografted human tumors and has the potential to be an effective animal model for cancer therapy. Wild-type and immunodeficient pigs were injected subcutaneously in the left ear with human melanoma cells (A375SM cells) and in the right ear with human pancreatic carcinoma cells (PANC-1). All immunodeficient pigs developed tumors that were verified by histology and immunohistochemistry. Nonaffected littermates did not develop tumors. Immunodeficient pigs, which do not reject xenografted human tumors, have the potential to become an extremely useful animal model for cancer therapy because of their similarity in size, anatomy, and physiology to humans.
doi:10.1089/biores.2012.9902
PMCID: PMC3559234  PMID: 23514746
immunodeficient swine; large-animal cancer model; melanoma; pancreatic carcinoma; xenografts
2.  Concise Review: Wharton’s Jelly-Derived Cells Are a Primitive Stromal Cell Population 
Stem Cells (Dayton, Ohio)  2007;26(3):591-599.
Here, the literature was reviewed to evaluate whether a population of mesenchymal stromal cells derived from Wharton’s jelly cells (WJCs) is a primitive stromal population. A clear case can be made for WJCs as a stromal population since they display the characteristics of MSCs as defined by the International Society for Cellular Therapy; for example, they grow as adherent cells with mesenchymal morphology, they are self-renewing, they express cell surface markers displayed by MSCs, and they may be differentiated into bone, cartilage, adipose, muscle, and neural cells. Like other stromal cells, WJCs support the expansion of other stem cells, such as hematopoietic stem cells, are well-tolerated by the immune system, and they have the ability to home to tumors. In contrast to bone marrow MSCs, WJCs have greater expansion capability, faster growth in vitro, and may synthesize different cytokines. WJCs are therapeutic in several different pre-clinical animal models of human disease such as neurodegenerative disease, cancer, heart disease, etc. The preclinical work suggests that the WJCs are therapeutic via trophic rescue and immune modulation. In summary, WJCs meet the definition of MSCs. Since WJCs expand faster and to a greater extent than adult-derived MSCs, these findings suggest that WJCs are a primitive stromal cell population with therapeutic potential. Further work is needed to determine whether WJCs engraft long-term and display self-renewal and multipotency in vivo and, as such, demonstrate whether Wharton’s jelly cells are a true stem cell population.
doi:10.1634/stemcells.2007-0439
PMCID: PMC3311226  PMID: 18065397
Mesenchymal stromal cells; Perinatal cells; Discarded tissue; Stromal cells
3.  Carbon dioxide hydrogenation to aromatic hydrocarbons by using an iron/iron oxide nanocatalyst 
Summary
The quest for renewable and cleaner energy sources to meet the rapid population and economic growth is more urgent than ever before. Being the most abundant carbon source in the atmosphere of Earth, CO2 can be used as an inexpensive C1 building block in the synthesis of aromatic fuels for internal combustion engines. We designed a process capable of synthesizing benzene, toluene, xylenes and mesitylene from CO2 and H2 at modest temperatures (T = 380 to 540 °C) employing Fe/Fe3O4 nanoparticles as catalyst. The synthesis of the catalyst and the mechanism of CO2-hydrogenation will be discussed, as well as further applications of Fe/Fe3O4 nanoparticles in catalysis.
doi:10.3762/bjnano.5.88
PMCID: PMC4077464  PMID: 24991513
aromatic hydrocarbons; carbon dioxide reduction; heterogenous catalysis; iron/iron oxide nanocatalyst
4.  Stem Cells in the Umbilical Cord 
Stem cell reviews  2006;2(2):155-162.
Stem cells are the next frontier in medicine. Stem cells are thought to have great therapeutic and biotechnological potential. This will not only to replace damaged or dysfunctional cells, but also rescue them and/or deliver therapeutic proteins after they have been engineered to do so. Currently, ethical and scientific issues surround both embryonic and fetal stem cells and hinder their widespread implementation. In contrast, stem cells recovered postnatally from the umbilical cord, including the umbilical cord blood cells, amnion/placenta, umbilical cord vein, or umbilical cord matrix cells, are a readily available and inexpensive source of cells that are capable of forming many different cell types (i.e., they are “multipotent”). This review will focus on the umbilical cord-derived stem cells and compare those cells with adult bone marrow-derived mesenchymal stem cells.
doi:10.1007/s12015-006-0022-y
PMCID: PMC3753204  PMID: 17237554
Umbilical cord matrix cells; Wharton’s Jelly; mesenchymal stem cells; umbilical cord blood cells
5.  Nanoscopic surfactant behavior of the porin MspA in aqueous media 
Summary
The mycobacterial porin MspA is one of the most stable channel proteins known to date. MspA forms vesicles at low concentrations in aqueous buffers. Evidence from dynamic light scattering, transmission electron microscopy and zeta-potential measurements by electrophoretic light scattering indicate that MspA behaves like a nanoscale surfactant. The extreme thermostability of MspA allows these investigations to be carried out at temperatures as high as 343 K, at which most other proteins would quickly denature. The principles of vesicle formation of MspA as a function of temperature and the underlying thermodynamic factors are discussed here. The results obtained provide crucial evidence in support of the hypothesis that, during vesicle formation, nanoscopic surfactant molecules, such as MspA, deviate from the principles underlined in classical surface chemistry.
doi:10.3762/bjnano.4.30
PMCID: PMC3678404  PMID: 23766950
charge-interaction; hydrophobic interaction; liposome-type cluster; protein cluster; supramolecular; temperature influence; zeta potential
6.  A Cell-Delivered and –Activated SN38-Dextran Prodrug Increases Survival in a Murine Disseminated Pancreatic Cancer Model 
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 we demonstrate a system based on cell delivery that can carry both a prodrug and an activating enzyme to the cancer site. Raw264.7 cells (mouse monocyte/macrophage like cells, Mo/Ma) were engineered to express intracellular rabbit carboxylesterase (InCE), which is a potent activator of the prodrug irinotecan to SN38. InCE expression was regulated by the TetOn® system, which silences the gene unless a tetracycline, such as doxycycline, is present. Concurrently, an irinotecan-like prodrug, conjugated to dextran, was synthesized that could be loaded into the cytoplasm of Mo/Ma. To test the system, a murine pancreatic cancer model was generated by intraperitoneal (i.p.) injection of Pan02 cells. Engineered Mo/Ma were loaded with the prodrug and were injected i.p. Two days later, doxycycline was given i.p. to activate InCE, which activated the prodrug. A survival study demonstrated that this system significantly increased survival in a murine pancreatic cancer model. Thus, for the first time, a prodrug/activating enzyme system self-contained within tumor-homing cells has been demonstrated that can prolong the life of i.p. pancreatic tumor bearing mice.
doi:10.1002/smll.201101879
PMCID: PMC3583224  PMID: 22238072
Prodrug Therapy; Cytotherapy; Pancreatic Cancer; Cancer Targeting
7.  A self-contained enzyme activating prodrug cytotherapy for preclinical melanoma 
Molecular biology reports  2011;39(1):157-165.
Gene-directed enzyme prodrug therapy (GDEPT) has been investigated as a means of cancer treatment without affecting normal tissues. This system is based on the delivery of a suicide gene, a gene encoding an enzyme which is able to convert its substrate from non-toxic prodrug to cytotoxin. In this experiment, we have developed a targeted suicide gene therapeutic system that is completely contained within tumor-tropic cells and have tested this system for melanoma therapy in a preclinical model. First, we established double stable RAW264.7 monocyte/macrophage-like cells (Mo/Ma) containing a Tet-On® Advanced system for intracellular carboxylesterase (InCE) expression. Second, we loaded a prodrug into the delivery cells, double stable Mo/Ma. Third, we activated the enzyme system to convert the prodrug, irinotecan, to the cytotoxin, SN-38. Our double stable Mo/Ma homed to the lung melanomas after 1 day and successfully delivered the prodrug-activating enzyme/prodrug package to the tumors. We observed that our system significantly reduced tumor weights and numbers as targeted tumor therapy after activation of the InCE. Therefore, we propose that this system may be a useful targeted melanoma therapy system for pulmonary metastatic tumors with minimal side effects, particularly if it is combined with other treatments.
doi:10.1007/s11033-011-0720-7
PMCID: PMC3222711  PMID: 21567204
B16-F10; Mouse lung melanoma; Mouse monocytes; Targeted cell delivery; Suicide therapy
8.  Magnetic-Fe/Fe3O4-nanoparticle-bound SN38 as carboxylesterase-cleavable prodrug for the delivery to tumors within monocytes/macrophages 
Summary
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/Fe3O4 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.
doi:10.3762/bjnano.3.51
PMCID: PMC3388369  PMID: 23016149
cell-based delivery; chemotherapeutic prodrug; magnetic Fe/Fe3O4 nanoparticles; SN38
9.  Cell-delivered magnetic nanoparticles caused hyperthermia-mediated increased survival in a murine pancreatic cancer model 
Using magnetic nanoparticles to absorb alternating magnetic field energy as a method of generating localized hyperthermia has been shown to be a potential cancer treatment. This report demonstrates a system that uses tumor homing cells to actively carry iron/iron oxide nanoparticles into tumor tissue for alternating magnetic field treatment. Paramagnetic iron/ iron oxide nanoparticles were synthesized and loaded into RAW264.7 cells (mouse monocyte/ macrophage-like cells), which have been shown to be tumor homing cells. A murine model of disseminated peritoneal pancreatic cancer was then generated by intraperitoneal injection of Pan02 cells. After tumor development, monocyte/macrophage-like cells loaded with iron/ iron oxide nanoparticles were injected intraperitoneally and allowed to migrate into the tumor. Three days after injection, mice were exposed to an alternating magnetic field for 20 minutes to cause the cell-delivered nanoparticles to generate heat. This treatment regimen was repeated three times. A survival study demonstrated that this system can significantly increase survival in a murine pancreatic cancer model, with an average post-tumor insertion life expectancy increase of 31%. This system has the potential to become a useful method for specifically and actively delivering nanoparticles for local hyperthermia treatment of cancer.
doi:10.2147/IJN.S28344
PMCID: PMC3265998  PMID: 22287840
cytotherapy; pancreatic cancer; disseminated peritoneal carcinomatosis; targeted magnetic hyperthermia; nanoparticles
10.  Attenuation of Mouse Melanoma by A/C Magnetic Field after Delivery of Bi-Magnetic Nanoparticles by Neural Progenitor Cells 
ACS nano  2010;4(12):7093-7104.
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/Fe3O4 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 hours) after the last of three AMF exposures.
doi:10.1021/nn100870z
PMCID: PMC3011034  PMID: 21058696
nanotechnology; cell-based; targeted delivery; magnetic nanoparticles; magnetic hyperthermia; melanoma; neural progenitor cells
11.  A/C magnetic hyperthermia of melanoma mediated by iron(0)/iron oxide core/shell magnetic nanoparticles: a mouse study 
BMC Cancer  2010;10:119.
Background
There is renewed interest in magnetic hyperthermia as a treatment modality for cancer, especially when it is combined with other more traditional therapeutic approaches, such as the co-delivery of anticancer drugs or photodynamic therapy.
Methods
The influence of bimagnetic nanoparticles (MNPs) combined with short external alternating magnetic field (AMF) exposure on the growth of subcutaneous mouse melanomas (B16-F10) was evaluated. Bimagnetic Fe/Fe3O4 core/shell nanoparticles were designed for cancer targeting after intratumoral or intravenous administration. Their inorganic center was protected against rapid biocorrosion by organic dopamine-oligoethylene glycol ligands. TCPP (4-tetracarboxyphenyl porphyrin) units were attached to the dopamine-oligoethylene glycol ligands.
Results
The magnetic hyperthermia results obtained after intratumoral injection indicated that micromolar concentrations of iron given within the modified core-shell Fe/Fe3O4 nanoparticles caused a significant anti-tumor effect on murine B16-F10 melanoma with three short 10-minute AMF exposures. We also observed a decrease in tumor size after intravenous administration of the MNPs followed by three consecutive days of AMF exposure 24 hrs after the MNPs injection.
Conclusions
These results indicate that intratumoral administration of surface modified MNPs can attenuate mouse melanoma after AMF exposure. Moreover, we have found that after intravenous administration of micromolar concentrations, these MNPs are capable of causing an anti-tumor effect in a mouse melanoma model after only a short AMF exposure time. This is a clear improvement to state of the art.
doi:10.1186/1471-2407-10-119
PMCID: PMC2859385  PMID: 20350328

Results 1-11 (11)