Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy

Cancer is responsible for a significant proportion of death all over the world. Therefore, strategies to improve its treatment are highly desired. The use of nanocarriers to deliver anticancer treatments has been extensively investigated and improved since the approval of the first liposomal formulation for cancer treatment in 1995. Radiotherapy (RT) is present in the disease management strategy of around 50% of cancer patients. In the present review, we bring the state-of-the-art information on the combination of nanocarrier-assisted delivery of molecules and RT. We start with formulations designed to encapsulate single or multiple molecules that, once delivered to the tumor site, act directly on the cells to improve the effects of RT. Then, we describe formulations designed to modulate the tumor microenvironment by delivering oxygen or to boost the abscopal effect. Finally, we present how RT can be employed to trigger molecule delivery from nanocarriers or to modulate the EPR effect.

ssRNA/DNA-Sensors via Embedded Strand-Displacement Programs in CRISPR/Cas9 Guides

RNA and DNA profiles can help classify a variety of biological states, including disease, metabolism and cell type. In a proof-of-concept study on novel genetically encodable components for detecting single-stranded oligonucleotides, we engineered switchable CRISPR guide RNA (swigRNA) with Cas9 affinity that is conditional on sensing an oligo trigger molecule (trigRNA or trigDNA). RNA- and DNA-sensing swigRNAs that serve as off-to-on and on-to-off switches for Cas9 cleavage were achieved by computational design of hybridization dependencies in the guide. This study highlights functional swigRNA structures that implement toehold-gated strand-displacement with their triggers, and should merit further engineering and kinetic characterization.

MIXED LANGMUIR-BLODGETT FILMS OF CU-3,5-BISTETRABUTYL PHENYLPORPHYRIN,ARACHIDATEACIDAND HEXATRIACONTANE IN ORDINARY ENVIRONMENT: AUV VISIBLE STUDY

> Abstrak. Telah dilakukan studi terhadap multilapis film Langmuir-Blodgett pada kondisi eksperimen seharihari menggunakan campuran Cu-3,5-bistetra-butil fenilporpirin, asam arakidat dengan dan atau tanpa inisiator,heksatriakantone. Campuran multilapis film (perbandingan molar porpirin : asam arachidic : heksatriakantone, 1,5 : 10, r, dimana r = 0, 0,5) terdiri dari 4, 20 dan 40 lapis berhasil di transfer ke atas kaca preparat sebagai Langmuir Blodgett film dan dilakukan karakterisasi dengan spektroskopi sinar tampak (UV-visible spectroscopy). Luas daerah per molekul porpirin adalah15-21 Å2. Campuran pertama (porpirin : asam arakidat) memberikan multilapisyang baik, sedangkan campuran dengan adanya inisiator tidak menghasilkan 20 dan 40 lapisan seperti prediksi. Beberapa kemungkinan penyebab hasil tidak optimum seperti tingkat kebersihan (cleanliness), kondisi isotermaldan kecepatan kompresi saat pembentukan multilapis film akan di bahas.Kata-kata kunci: Langmuir-Blodgett Films, multilapis, Cu-3,5-bistetrabutyl-phenylporphyrinAbstract. The study of mixed Langmuir-Blodgett Films multilayer was conducted in ordinary experiment conditions by using metallo-porphyrin derivative (3,5-bistetrabutyl-phenylporphyrin with Cu as central metal) andarachidate acid with and without trigger molecule, hexatriacontane. We demonstrated that the mixed multilayer which consist of 4, 20 and 40 layers for each mixed solution (molar ratio porphyrin : arachidic acid :hexatriancontane, 1,5 : 10 : r, where r is 0, 0.5) successfully transfers into glass plates as Langmuir-Blodgett Films and characterized the transferred films using UV visible spectroscopy. The area per monolayer porphyrin moleculeis approximately 15-21 Å2. The first mixed solution (porhyrin: arachidic acid) produced good multilayer while the second mixed solution (porphyrin : arachidic acid : trigger molecule, hexatriancontane) did not produce 20 and 40layers as it was expected. Some possible problems such as cleanliness, isotherms condition and compression speed of forming multilayer will be discussed.Key words:Langmuir-Blodgett Films, multilayer, Cu-3,5-bistetrabutyl phenylporphyrin

FcαRI (CD89) as a Novel Trigger Molecule for Bispecific Antibody Therapy

Promising results from clinical trials with unconjugated antibodies stimulated renewed interest in immune effector mechanisms of monoclonal antibodies (MoAbs). We investigated the potential of IgA as antibody isotype for cell- or complement-mediated tumor cell lysis and assessed the potential of its myeloid Fc receptor, FcαRI (CD89), as trigger molecule for bispecific antibody (BsAb)-mediated immunotherapy. Comparing hapten-directed antibodies of human IgA2 with IgG1 or IgG3 isotypes, we found all three to mediate effective killing of sensitized tumor target cells in whole blood assays. Analysis of effector mechanisms showed IgG-mediated lysis to be predominantly complement-dependent, whereas IgA-dependent killing was primarily effector cell-mediated. A comparison of effector cell populations in antibody-dependent cell-mediated cytotoxicity (ADCC) showed neutrophils to be most important for IgA-dependent tumor cell killing, involving FcαRI as shown with Fc receptor blocking antibodies. Reverse ADCC experiments against target cells sensitized with Fc receptor antibodies, or assays with FcαRI-directed bispecific antibodies confirmed FcαRI as effective trigger molecule in polymorphonuclear neutrophil (PMN)-mediated lysis. During granulocyte colony-stimulating factor (G-CSF ) therapy, (FcαRI × HER-2/neu) bispecific antibodies induced enhanced killing of HER-2/neu positive SK-BR–3 breast cancer cells in whole blood assays. This enhanced cytotoxicity was paralleled by increased PMN counts, which lead to higher effector to target cell ratios in G-CSF–primed blood. Furthermore, bispecific antibodies, directed to FcαRI and Candida albicans, enhanced neutrophils' phagocytosis of fungi. In summary, these results identify IgA as an effective antibody isotype for immunotherapy, working primarily via FcαRI on neutrophils. They suggest FcαRI-directed bispecific antibodies and G-CSF to be an attractive combination for malignant or infectious diseases.

FcαRI (CD89) as a Novel Trigger Molecule for Bispecific Antibody Therapy

Promising results from clinical trials with unconjugated antibodies stimulated renewed interest in immune effector mechanisms of monoclonal antibodies (MoAbs). We investigated the potential of IgA as antibody isotype for cell- or complement-mediated tumor cell lysis and assessed the potential of its myeloid Fc receptor, FcαRI (CD89), as trigger molecule for bispecific antibody (BsAb)-mediated immunotherapy. Comparing hapten-directed antibodies of human IgA2 with IgG1 or IgG3 isotypes, we found all three to mediate effective killing of sensitized tumor target cells in whole blood assays. Analysis of effector mechanisms showed IgG-mediated lysis to be predominantly complement-dependent, whereas IgA-dependent killing was primarily effector cell-mediated. A comparison of effector cell populations in antibody-dependent cell-mediated cytotoxicity (ADCC) showed neutrophils to be most important for IgA-dependent tumor cell killing, involving FcαRI as shown with Fc receptor blocking antibodies. Reverse ADCC experiments against target cells sensitized with Fc receptor antibodies, or assays with FcαRI-directed bispecific antibodies confirmed FcαRI as effective trigger molecule in polymorphonuclear neutrophil (PMN)-mediated lysis. During granulocyte colony-stimulating factor (G-CSF ) therapy, (FcαRI × HER-2/neu) bispecific antibodies induced enhanced killing of HER-2/neu positive SK-BR–3 breast cancer cells in whole blood assays. This enhanced cytotoxicity was paralleled by increased PMN counts, which lead to higher effector to target cell ratios in G-CSF–primed blood. Furthermore, bispecific antibodies, directed to FcαRI and Candida albicans, enhanced neutrophils' phagocytosis of fungi. In summary, these results identify IgA as an effective antibody isotype for immunotherapy, working primarily via FcαRI on neutrophils. They suggest FcαRI-directed bispecific antibodies and G-CSF to be an attractive combination for malignant or infectious diseases.