39 research outputs found
protocol of a prospective, longitudinal study
Background Natural killer (NK) cells comprise the main components of
lymphocyte-mediated nonspecific immunity. Through their effector function they
play a crucial role combating bacterial and viral challenges. They are also
thought to be key contributors to the systemic spinal cord injury-induced
immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to
infection and extends to the post-acute and chronic phases after SCI. Methods
and design The prospective study of NK cell function after traumatic SCI was
carried out in two centers in Berlin, Germany. SCI patients and control
patients with neurologically silent vertebral fracture also undergoing
surgical stabilization were enrolled. Furthermore healthy controls were
included to provide reference data. The NK cell function was assessed at 7
(5–9) days, 14 days (11–28) days, and 10 (8–12) weeks post-trauma. Clinical
documentation included the American Spinal Injury Association (ASIA)
impairment scale (AIS), neurological level of injury, infection status,
concomitant injury, and medications. The primary endpoint of the study is
CD107a expression by NK cells (cytotoxicity marker) 8–12 weeks following SCI.
Secondary endpoints are the NK cell’s TNF-α and IFN-γ production by the NK
cells 8–12 weeks following SCI. Discussion The protocol of this study was
developed to investigate the hypotheses whether i) SCI impairs NK cell
function throughout the post-acute and sub-acute phases after SCI and ii) the
degree of impairment relates to lesion height and severity. A deeper
understanding of the SCI-IDS is crucial to enable strategies for prevention of
infections, which are associated with poor neurological outcome and elevated
mortality. Trial registration DRKS00009855
Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo
In the continuing search for effective cancer treatments, we report the rational
engineering of a multifunctional nanoparticle that combines traditional
chemotherapy with cell targeting and anti-adhesion functionalities. Very late
antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone
marrow stroma confers MM cells with cell-adhesion-mediated drug resistance
(CAM-DR). In our design, we used micellar nanoparticles as dynamic
self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin
(Dox) conjugates, simultaneously, to selectively target MM cells and to overcome
CAM-DR. Dox was conjugated to the nanoparticles through an acid-sensitive
hydrazone bond. VLA-4-antagonist peptides were conjugated via a multifaceted
synthetic procedure for generating precisely controlled number of targeting
functionalities. The nanoparticles were efficiently internalized by MM cells and
induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced
DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional
nanoparticles overcame CAM-DR, and were more efficacious than Dox when MM cells
were cultured on fibronectin-coated plates. Finally, in a MM xenograft model,
nanoparticles preferentially homed to MM tumors with ∼10 fold more drug
accumulation and demonstrated dramatic tumor growth inhibition with a reduced
overall systemic toxicity. Altogether, we demonstrate the disease driven
engineering of a nanoparticle-based drug delivery system, enabling the model of
an integrative approach in the treatment of MM
Best Practices in Cancer Nanotechnology: Perspective from NCI Nanotechnology Alliance
Historically, treatment of patients with cancer using chemotherapeutic agents has been associated with debilitating and systemic toxicities, poor bioavailability, and unfavorable pharmacokinetics. Nanotechnology-based drug delivery systems, on the other hand, can specifically target cancer cells while avoiding their healthy neighbors, avoid rapid clearance from the body, and be administered without toxic solvents. They hold immense potential in addressing all of these issues which has hampered further development of chemotherapeutics. Furthermore, such drug delivery systems will lead to cancer therapeutic modalities which are not only less toxic to the patient but also significantly more efficacious. In addition to established therapeutic modes of action, nanomaterials are opening up entirely new modalities of cancer therapy, such as photodynamic and hyperthermia treatments. Furthermore, nanoparticle carriers are also capable of addressing several drug delivery problems which could not be effectively solved in the past and include overcoming formulation issues, multi-drug-resistance phenomenon and penetrating cellular barriers that may limit device accessibility to intended targets such as the blood-brain-barrier. The challenges in optimizing design of nanoparticles tailored to specific tumor indications still remain; however, it is clear that nanoscale devices carry a significant promise towards new ways of diagnosing and treating cancer. This review focuses on future prospects of using nanotechnology in cancer applications and discusses practices and methodologies used in the development and translation of nanotechnology-based therapeutics
A Novel Peptide Enhances Therapeutic Efficacy of Liposomal Anti-Cancer Drugs in Mice Models of Human Lung Cancer
Lung cancer is the leading cause of cancer-related mortality worldwide. The lack of tumor specificity remains a major drawback for effective chemotherapies and results in dose-limiting toxicities. However, a ligand-mediated drug delivery system should be able to render chemotherapy more specific to tumor cells and less toxic to normal tissues. In this study, we isolated a novel peptide ligand from a phage-displayed peptide library that bound to non-small cell lung cancer (NSCLC) cell lines. The targeting phage bound to several NSCLC cell lines but not to normal cells. Both the targeting phage and the synthetic peptide recognized the surgical specimens of NSCLC with a positive rate of 75% (27 of 36 specimens). In severe combined immunodeficiency (SCID) mice bearing NSCLC xenografts, the targeting phage specifically bound to tumor masses. The tumor homing ability of the targeting phage was inhibited by the cognate synthetic peptide, but not by a control or a WTY-mutated peptide. When the targeting peptide was coupled to liposomes carrying doxorubicin or vinorelbine, the therapeutic index of the chemotherapeutic agents and the survival rates of mice with human lung cancer xenografts markedly increased. Furthermore, the targeting liposomes increased drug accumulation in tumor tissues by 5.7-fold compared with free drugs and enhanced cancer cell apoptosis resulting from a higher concentration of bioavailable doxorubicin. The current study suggests that this tumor-specific peptide may be used to create chemotherapies specifically targeting tumor cells in the treatment of NSCLC and to design targeted gene transfer vectors or it may be used one in the diagnosis of this malignancy
Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women
<p>Abstract</p> <p>Background</p> <p>Several studies have determined that dietary intake of B vitamins may be associated with breast cancer risk as a result of interactions between <it>5,10-methylenetetrahydrofolate reductase (MTHFR) </it>and <it>methionine synthase </it>(<it>MTR</it>) in the one-carbon metabolism pathway. However, the association between B vitamin intake and breast cancer risk in Brazilian women in particular has not yet been investigated.</p> <p>Methods</p> <p>A case-control study was conducted in São Paulo, Brazil, with 458 age-matched pairs of Brazilian women. Energy-adjusted intakes of folate, vitamin B<sub>6</sub>, and vitamin B<sub>12 </sub>were derived from a validated Food Frequency Questionnaire (FFQ). Genotyping was completed for <it>MTHFR </it>A1298C and C677T, and <it>MTR </it>A2756G polymorphisms. A logistical regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).</p> <p>Results</p> <p>Neither dietary intake of folate, vitamin B<sub>6</sub>, or vitamin B<sub>12 </sub>nor <it>MTHFR </it>polymorphisms were independently associated with breast cancer risk. Analysis stratified by menopausal status showed a significant association between placement in the highest tertile of folate intake and risk of breast cancer in premenopausal women (OR = 2.17, 95% CI: 1.23–3.83; <it>P</it><sub><it>trend </it></sub>= 0.010). The <it>MTR </it>2756GG genotype was associated with a higher risk of breast cancer than the 2756AA genotype (OR = 1.99, 95% CI = 1.01–3.92; <it>P</it><sub><it>trend </it></sub>= 0.801), and statistically significant interactions with regard to risk were observed between the <it>MTHFR </it>A1298C polymorphism and folate (P = 0.024) or vitamin B<sub>6 </sub>(P = 0.043), and between the <it>MTHFR </it>C677T polymorphism and folate (P = 0.043) or vitamin B<sub>12 </sub>(P = 0.022).</p> <p>Conclusion</p> <p><it>MTHFR </it>polymorphisms and dietary intake of folate, vitamin B<sub>6</sub>, and vitamin B<sub>12 </sub>had no overall association with breast cancer risk. However, increased risk was observed in total women with the <it>MTR </it>2756GG genotype and in premenopausal women with high folate intake. These findings, as well as significant interactions between <it>MTHFR </it>polymorphisms and B vitamins, warrant further investigation.</p
Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis
Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy
Pharmacokinetics, Tissue Distribution and Therapeutic Effect of Cationic Thermosensitive Liposomal Doxorubicin Upon Mild Hyperthermia
Chimeric Virus-Like Particles Made Using GAG and M1 Capsid Proteins Providing Dual Drug Delivery and Vaccination Platform
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