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Article ; Online: A Prospective Study of Humoral and Cellular Immune Responses to Hepatitis B Vaccination in Habitual Marijuana Smokers.

Kiertscher, Sylvia M / Gangalum, Pallavi R / Ibrahim, Grace / Tashkin, Donald P / Roth, Michael D

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

2018 Volume 13, Issue 2, Page(s) 219–229

Abstract: Exposure to ... ...

Abstract	Exposure to Δ
MeSH term(s)	Adult ; Female ; Hepatitis B Antibodies/blood ; Hepatitis B Vaccines/immunology ; Humans ; Immunity, Cellular/drug effects ; Immunity, Humoral/drug effects ; Male ; Marijuana Smoking/immunology ; Middle Aged ; Prospective Studies ; Young Adult
Chemical Substances	Hepatitis B Antibodies ; Hepatitis B Vaccines
Language	English
Publishing date	2018-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2227405-4
ISSN	1557-1904 ; 1557-1890
ISSN (online)	1557-1904
ISSN	1557-1890
DOI	10.1007/s11481-018-9776-7
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Article ; Online: HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug.

Ding, Hui / Gangalum, Pallavi R / Galstyan, Anna / Fox, Irving / Patil, Rameshwar / Hubbard, Paul / Murali, Ramachandran / Ljubimova, Julia Y / Holler, Eggehard

Nanomedicine : nanotechnology, biology, and medicine

2017 Volume 13, Issue 2, Page(s) 631–639

Abstract: HER2+ breast cancer is one of the most aggressive forms of breast cancer. The new polymalic acid-based mini nanodrug copolymers are synthesized and specifically characterized to inhibit growth of HER2+ breast cancer. These mini nanodrugs are highly ... ...

Abstract	HER2+ breast cancer is one of the most aggressive forms of breast cancer. The new polymalic acid-based mini nanodrug copolymers are synthesized and specifically characterized to inhibit growth of HER2+ breast cancer. These mini nanodrugs are highly effective and in the clinic may substitute for trastuzumab (the marketed therapeutic antibody) and antibody-targeted nanobioconjugates. Novel mini nanodrugs are designed to have slender shape and small size. HER2+ cells were recognized by the polymer-attached trastuzumab-mimetic 12-mer peptide. Synthesis of the nascent cell-transmembrane HER2/neu receptors by HER2+ cells was inhibited by antisense oligonucleotides that prevented cancer cell proliferation and significantly reduced tumor size by more than 15 times vs. untreated control or PBS-treated group. We emphasize that the shape and size of mini nanodrugs can enhance penetration of multiple bio-barriers to facilitate highly effective treatment. Replacement of trastuzumab by the mimetic peptide favors reduced production costs and technical efforts, and a negligible immune response.
MeSH term(s)	Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Breast Neoplasms/drug therapy ; Cell Line, Tumor ; Humans ; Nanoparticles/chemistry ; Peptides/therapeutic use ; Receptor, ErbB-2 ; Trastuzumab/administration & dosage ; Trastuzumab/pharmacokinetics
Chemical Substances	Antibodies, Monoclonal, Humanized ; Peptides ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
Language	English
Publishing date	2017-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2183417-9
ISSN	1549-9642 ; 1549-9634
ISSN (online)	1549-9642
ISSN	1549-9634
DOI	10.1016/j.nano.2016.07.013
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Article ; Online: Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu.

Divekar, Anagha A / Dubey, Shweta / Gangalum, Pallavi R / Singh, Ram Raj

Journal of immunology (Baltimore, Md. : 1950)

2010 Volume 186, Issue 2, Page(s) 924–930

Abstract: Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance to self-Ags and activation of autoreactive T cells. Regulatory T (Treg) cells play a critical role in controlling the activation of autoreactive T cells. In ... ...

Abstract	Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance to self-Ags and activation of autoreactive T cells. Regulatory T (Treg) cells play a critical role in controlling the activation of autoreactive T cells. In this study, we investigated mechanisms of potential Treg cell defects in systemic lupus erythematosus using MRL-Fas(lpr/lpr) (MRL/lpr) and MRL-Fas(+/+) mouse models. We found a significant increase in CD4(+)CD25(+)Foxp3(+) Treg cells, albeit with an altered phenotype (CD62L(-)CD69(+)) and with a reduced suppressive capacity, in the lymphoid organs of MRL strains compared with non-autoimmune C3H/HeOuj mice. A search for mechanisms underlying the altered Treg cell phenotype in MRL/lpr mice led us to find a profound reduction in Dicer expression and an altered microRNA (miRNA, miR) profile in MRL/lpr Treg cells. Despite having a reduced level of Dicer, MRL/lpr Treg cells exhibited a significant overexpression of several miRNAs, including let-7a, let-7f, miR-16, miR-23a, miR-23b, miR-27a, and miR-155. Using computational approaches, we identified one of the upregulated miRNAs, miR-155, that can target CD62L and may thus confer the altered Treg cell phenotype in MRL/lpr mice. In fact, the induced overexpression of miR-155 in otherwise normal (C3H/HeOuj) Treg cells reduced their CD62L expression, which mimics the altered Treg cell phenotype in MRL/lpr mice. These data suggest a role of Dicer and miR-155 in regulating Treg cell phenotype. Furthermore, simultaneous appearance of Dicer insufficiency and miR-155 overexpression in diseased mice suggests a Dicer-independent alternative mechanism of miRNA regulation under inflammatory conditions.
MeSH term(s)	Animals ; Computational Biology/methods ; DEAD-box RNA Helicases/deficiency ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/physiology ; Endoribonucleases/deficiency ; Endoribonucleases/genetics ; Endoribonucleases/physiology ; Immunophenotyping ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/pathology ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/immunology ; Lupus Erythematosus, Systemic/pathology ; Lymphoid Tissue/immunology ; Lymphoid Tissue/metabolism ; Lymphoid Tissue/pathology ; Mice ; Mice, Inbred C3H ; Mice, Inbred MRL lpr ; MicroRNAs/biosynthesis ; MicroRNAs/genetics ; MicroRNAs/physiology ; Ribonuclease III ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/pathology
Chemical Substances	MicroRNAs ; Mirn155 microRNA, mouse ; Endoribonucleases (EC 3.1.-) ; Dicer1 protein, mouse (EC 3.1.26.3) ; Ribonuclease III (EC 3.1.26.3) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2010-12-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1002218
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Article ; Online: Platelet-activating factor receptor contributes to antileishmanial function of miltefosine.

Gangalum, Pallavi R / de Castro, Waldionê / Vieira, Leda Q / Dey, Ranadhir / Rivas, Luis / Singh, Shailza / Majumdar, Subrata / Saha, Bhaskar

Journal of immunology (Baltimore, Md. : 1950)

2015 Volume 194, Issue 12, Page(s) 5961–5967

Abstract: Miltefosine [hexadecylphosphocholine (HPC)] is the only orally bioavailable drug for the disease visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani. Although miltefosine has direct leishmanicidal effects, evidence is ... ...

Abstract	Miltefosine [hexadecylphosphocholine (HPC)] is the only orally bioavailable drug for the disease visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani. Although miltefosine has direct leishmanicidal effects, evidence is mounting for its immune system-dependent effects. The mechanism of such indirect antileishmanial effects of miltefosine remains to be discovered. As platelet-activating factor and HPC share structural semblances and both induce killing of intracellular Leishmania, we surmised that platelet-activating factor (PAF) receptor had a significant role in the antileishmanial function of miltefosine. The proposition was supported by molecular dynamic simulation of HPC docking into PAF receptor and by comparison of its leishmanicidal function on PAF receptor-deficient macrophages and mice under HPC treatment. We observed that compared with wild-type macrophages, the PAF receptor-deficient macrophages showed 1) reduced binding of a fluorescent analog of HPC, 2) decreased TNF-α production, and 3) lower miltefosine-induced killing of L. donovani. Miltefosine exhibited significantly compromised leishmanicidal function in PAF receptor-deficient mice. An anti-PAF receptor Ab led to a significant decrease in miltefosine-induced intracellular Leishmania killing and IFN-γ production in a macrophage-T cell coculture system. These results indicate significant roles for PAF receptor in the leishmanicidal activity of HPC. The findings open new avenues for a more rational understanding of the mechanism of action of this drug as well as for improved therapeutic strategies.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Antigens, Protozoan/immunology ; Antiprotozoal Agents/administration & dosage ; Antiprotozoal Agents/chemistry ; Antiprotozoal Agents/pharmacology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Gene Knockout Techniques ; Interferon-gamma/biosynthesis ; Leishmania donovani/immunology ; Leishmaniasis, Visceral/drug therapy ; Leishmaniasis, Visceral/genetics ; Leishmaniasis, Visceral/immunology ; Leishmaniasis, Visceral/metabolism ; Ligands ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Models, Molecular ; Molecular Conformation ; Phosphorylcholine/administration & dosage ; Phosphorylcholine/analogs & derivatives ; Phosphorylcholine/chemistry ; Phosphorylcholine/pharmacology ; Platelet Membrane Glycoproteins/antagonists & inhibitors ; Platelet Membrane Glycoproteins/chemistry ; Platelet Membrane Glycoproteins/deficiency ; Platelet Membrane Glycoproteins/metabolism ; Protein Binding ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/deficiency ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Antibodies, Monoclonal ; Antigens, Protozoan ; Antiprotozoal Agents ; Ligands ; Platelet Membrane Glycoproteins ; Receptors, G-Protein-Coupled ; platelet activating factor receptor ; Phosphorylcholine (107-73-3) ; miltefosine (53EY29W7EC) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2015-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1401890
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Article: Advances in Imaging: Brain Tumors to Alzheimer's Disease.

Patil, Rameshwar / Koronyo, Yosef / Ljubimov, Alexander V / Salumbides, Brenda / Mamelak, Adam / Gangalum, Pallavi R / Ding, Hui / Portilla-Arias, Jose / Holler, Eggehard / Butte, Pramod / Koronyo-Hamaoui, Maya / Ljubimova, Julia Y / Black, Keith L

The Bangkok medical journal

2017 Volume 10, Page(s) 83–97

Abstract: Professor Black and colleagues have been working to improve the quality and sensitivity of imaging in the early detection of conditions from brain tumors to Alzheimer's disease to enhance treatment protocols and patient management. Professor Black et al ... ...

Abstract	Professor Black and colleagues have been working to improve the quality and sensitivity of imaging in the early detection of conditions from brain tumors to Alzheimer's disease to enhance treatment protocols and patient management. Professor Black et al introduced nanoparticles to improve MRI imaging. These nanoparticles consist of poly (b-L- malic acid (PMLA)) conjugates with monoclonal antibodies ((mAbs)) and Gd-DOTA. These are known as MRI nano-imaging agents (NIA). Most importantly, they can penetrate the endothelial blood-brain barrier (BBB) to reach brain tumors (primary or metastasis). This is effective in cases of brain tumors or breast cancer or other cancers such as lung cancer and gastric cancer having HER2 and/or EGFR positive crossing BBB. By the covalent conjugation of MR contrast (NIA), the MRI virtual biopsy can differentiate brain tumors from infections or other brain pathological conditions. The brain's intrinsic natural fluorescence such as NADH, FAD, lipopigments and porphyrin in the brain tissue can be identified by using time resolved fluorescence spectroscopy (TRFS) which is operated through the use of ultra-short laser. TRFS produces various color bands to differentiate the tumor from normal brain tissue in real time and registers the data on a 3D map. This is significant, as this will provide a greatly improved assessment methodology of tissue type. Consequently, this will potentially result in shorter operation times as well as more satisfactory tumor removal. In the detection of Alzheimer disease, amyloid plaque is deposited in retina tissue (including the RGC, RNFL and inner plexiform layer) which can produce a fluorescence effect by using curcumin as a contrast. This is then shown by human retina amyloid imaging device. Immunotherapies with glatiramer acetate (GA) have been shown to reduce amyloid deposits in brain and retinal AB deposits in mice. The study of advanced imaging technology and techniques including NIA, TRFS and the detection of amyloid plaque in Alzheimer disease are very important approaches to create a new era for diagnostic and therapeutic management of brain tumors and other cancers (HER2 and/or EGFR positive). This pioneering work by Professor Black, and colleagues, gives rise to a new hope for cancer patients for targeted therapy and for immunotherapies in Alzheimer's disease.
Language	English
Publishing date	2017-10-05
Publishing country	Thailand
Document type	Journal Article
ISSN	2228-9674
ISSN	2228-9674
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Article: Polymalic acid-based nano biopolymers for targeting of multiple tumor markers: an opportunity for personalized medicine?

Ljubimova, Julia Y / Ding, Hui / Portilla-Arias, Jose / Patil, Rameshwar / Gangalum, Pallavi R / Chesnokova, Alexandra / Inoue, Satoshi / Rekechenetskiy, Arthur / Nassoura, Tala / Black, Keith L / Holler, Eggehard

Journal of visualized experiments. 2014 June 13, , no. 88

2014

Abstract: Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs ...

Abstract	Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors.
Keywords	animal models ; biodegradability ; biopolymers ; breast neoplasms ; drugs ; genes ; humans ; immune response ; nanomedicine ; oligonucleotides ; precision medicine ; toxicity
Language	English
Dates of publication	2014-0613
Size	p. e50668.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/50668
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Curcumin Targeted, Polymalic Acid-Based MRI Contrast Agent for the Detection of Aβ Plaques in Alzheimer's Disease.

Patil, Rameshwar / Gangalum, Pallavi R / Wagner, Shawn / Portilla-Arias, Jose / Ding, Hui / Rekechenetskiy, Arthur / Konda, Bindu / Inoue, Satoshi / Black, Keith L / Ljubimova, Julia Y / Holler, Eggehard

Macromolecular bioscience

2015 Volume 15, Issue 9, Page(s) 1212–1217

Abstract: Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Aβ) plaques in Alzheimer's disease (AD). Its timely finding would be vital for patient survival and quality of ...

Abstract	Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Aβ) plaques in Alzheimer's disease (AD). Its timely finding would be vital for patient survival and quality of life. Curcumin (CUR), a common Indian spice effectively binds to Aβ plaques which is a hallmark of AD. To address this binding, we have designed a novel nanoimaging agent (NIA) based on nature-derived poly(β-l-malic acid) (PMLA) containing covalently attached gadolinium-DOTA(Gd-DOTA) and nature-derived CUR. The all-in-one agent recognizes and selectively binds to Aβ plaques and is detected by MRI. It efficiently detected Aβ plaques in human and mouse samples by an ex vivo staining. The method can be useful in clinic for safe and noninvasive diagnosis of AD.
MeSH term(s)	Alzheimer Disease/diagnosis ; Animals ; Brain/pathology ; Contrast Media/chemistry ; Curcumin/analogs & derivatives ; Curcumin/chemistry ; Heterocyclic Compounds/chemistry ; Humans ; Magnetic Resonance Imaging ; Malates/chemistry ; Mice ; Organometallic Compounds/chemistry ; Plaque, Amyloid/diagnosis ; Polymers/chemistry
Chemical Substances	Contrast Media ; Heterocyclic Compounds ; Malates ; Organometallic Compounds ; Polymers ; poly(malic acid) ; gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate (99J2XUF1JT) ; Curcumin (IT942ZTH98)
Language	English
Publishing date	2015-09
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2039130-4
ISSN	1616-5195 ; 1616-5187
ISSN (online)	1616-5195
ISSN	1616-5187
DOI	10.1002/mabi.201500062
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Article ; Online: Simultaneous blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme.

Chou, Szu-Ting / Patil, Rameshwar / Galstyan, Anna / Gangalum, Pallavi R / Cavenee, Webster K / Furnari, Frank B / Ljubimov, Vladimir A / Chesnokova, Alexandra / Kramerov, Andrei A / Ding, Hui / Falahatian, Vida / Mashouf, Leila / Fox, Irving / Black, Keith L / Holler, Eggehard / Ljubimov, Alexander V / Ljubimova, Julia Y

Journal of controlled release : official journal of the Controlled Release Society

2016 Volume 244, Issue Pt A, Page(s) 14–23

Abstract: Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. GBM tumors are also notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were ... ...

Abstract	Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. GBM tumors are also notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database. Two xenogeneic mouse models bearing intracranial human GBMs from cell lines LN229 and U87MG that expressed both CK2 and EGFR at different levels were used. Simultaneous knockdown of CK2α and EGFR/EGFRvIII suppressed their downstream prosurvival signaling. Treatment also markedly reduced the expression of programmed death-ligand 1 (PD-L1), a negative regulator of cytotoxic lymphocytes. Downregulation of CK2 and EGFR also caused deactivation of heat shock protein 90 (Hsp90) co-chaperone Cdc37, which may suppress the activity of key cellular kinases. Inhibition of either target was associated with downregulation of the other target as well, which may underlie the increased efficacy of the dual nanobioconjugate that is directed against both CK2 and EGFR. Importantly, the single nanodrugs, and especially the dual nanodrug, markedly suppressed the expression of the cancer stem cell markers c-Myc, CD133, and nestin, which could contribute to the efficacy of the treatments. In both tumor models, the nanobioconjugates significantly increased (up to 2-fold) animal survival compared with the PBS-treated control group. The versatile nanobioconjugates developed in this study, with the abilities of anti-cancer drug delivery across biobarriers and the inhibition of key tumor regulators, offer a promising nanotherapeutic approach to treat GBMs, and to potentially prevent drug resistance and retard the recurrence of brain tumors.
MeSH term(s)	Adult ; Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/therapeutic use ; Blood-Brain Barrier/metabolism ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Casein Kinase II/antagonists & inhibitors ; Casein Kinase II/genetics ; Cell Line, Tumor ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/genetics ; Female ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Humans ; Malates/chemistry ; Mice ; Mice, Nude ; Nanoconjugates/chemistry ; Nanoconjugates/therapeutic use ; Neoplastic Stem Cells ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/therapeutic use ; Polyethylene Glycols/chemistry ; Polymers/chemistry ; Signal Transduction ; Surface Properties
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents ; Malates ; Nanoconjugates ; Oligonucleotides, Antisense ; Polymers ; epidermal growth factor receptor VIII ; poly(malic acid) ; Polyethylene Glycols (3WJQ0SDW1A) ; ErbB Receptors (EC 2.7.10.1) ; Casein Kinase II (EC 2.7.11.1)
Language	English
Publishing date	2016-11-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2016.11.001
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Article ; Online: Polymalic acid-based nano biopolymers for targeting of multiple tumor markers: an opportunity for personalized medicine?

Journal of visualized experiments : JoVE

2014 , Issue 88

Abstract	Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors.
MeSH term(s)	Animals ; Biomarkers, Tumor/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/enzymology ; Female ; Gene Silencing ; Humans ; Malates/administration & dosage ; Malates/chemical synthesis ; Malates/chemistry ; Malates/metabolism ; Mice ; Mice, Nude ; Molecular Targeted Therapy/methods ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Oligonucleotides, Antisense/administration & dosage ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/genetics ; Physarum polycephalum/genetics ; Physarum polycephalum/metabolism ; Polymers/administration & dosage ; Polymers/chemical synthesis ; Polymers/chemistry ; Polymers/metabolism ; Precision Medicine/methods ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/biosynthesis ; Receptor, ErbB-2/genetics ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Biomarkers, Tumor ; Malates ; Oligonucleotides, Antisense ; Polymers ; poly(malic acid) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2014-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/50668
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Article ; Online: MRI virtual biopsy and treatment of brain metastatic tumors with targeted nanobioconjugates: nanoclinic in the brain.

Patil, Rameshwar / Ljubimov, Alexander V / Gangalum, Pallavi R / Ding, Hui / Portilla-Arias, Jose / Wagner, Shawn / Inoue, Satoshi / Konda, Bindu / Rekechenetskiy, Arthur / Chesnokova, Alexandra / Markman, Janet L / Ljubimov, Vladimir A / Li, Debiao / Prasad, Ravi S / Black, Keith L / Holler, Eggehard / Ljubimova, Julia Y

ACS nano

2015 Volume 9, Issue 5, Page(s) 5594–5608

Abstract: Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy, which can be often dangerous or even impossible. Such MRI enhancement(s) can result from ... ...

Abstract	Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy, which can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections, or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise noninvasive MRI diagnostic method, we have engineered a new class of poly(β-l-malic acid) polymeric nanoimaging agents (NIAs). The NIAs carrying attached MRI tracer are able to pass through the blood-brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative "MRI virtual biopsy" method is based on a nanoconjugate carrying MRI contrast agent gadolinium-DOTA and antibodies recognizing tumor-specific markers and extravasating through the BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this noninvasive method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in a significant increase in animal survival and markedly reduced immunostaining for several cancer stem cell markers. Novel NIAs could be useful for brain diagnostic MRI in the clinic without currently performed brain biopsies. This technology shows promise for differential MRI diagnosis and treatment of brain metastases and other pathologies when biopsies are difficult to perform.
MeSH term(s)	Animals ; Base Sequence ; Biopsy/methods ; Blood-Brain Barrier/metabolism ; Brain/pathology ; Brain Neoplasms/diagnosis ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Diagnosis, Differential ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Magnetic Resonance Imaging/methods ; Mice ; Nanoconjugates/chemistry ; Nanomedicine/methods ; Neoplasm Metastasis ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/metabolism ; Receptor, Epidermal Growth Factor/metabolism ; Receptor, ErbB-2/metabolism ; Survival Analysis
Chemical Substances	Nanoconjugates ; Oligonucleotides, Antisense ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2015-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.5b01872
Database	MEDical Literature Analysis and Retrieval System OnLINE

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