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Diêgo dos Santos Ferreira,1,2 Samilla Dornelas Faria,1 Sávia Caldeira de Araújo Lopes,1 Cláudia Salviano Teixeira,1 Angelo Malachias,3 Rogério Magalhães-Paniago,3 José Dias de Souza Filho,4 Bruno Luis de Jesus Pinto Oliveira,2 Alexander Ramos Guimarães,2 Peter Caravan,2 Lucas Antônio Miranda Ferreira,1 Ricardo José Alves,1 Mônica Cristina Oliveira1 1Department of Pharmaceutical Products, Faculty of Pharmacy,Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 2Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 3Department of Physics, 4Department of Chemistry, Institute of Exact Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Background: Despite recent advances in cancer therapy, the treatment of bone tumors remains a major challenge. A possible underlying hypothesis, limitation, and unmet need may be the inability of therapeutics to penetrate into dense bone mineral, which can lead to poor efficacy and high toxicity, due to drug uptake in healthy organs. The development of nanostructured formulations with high affinity for bone could be an interesting approach to overcome these challenges.Purpose: To develop a liposomal formulation with high affinity for hydroxyapatite and the ability to release doxorubicin (DOX) in an acidic environment for future application as a tool for treatment of bone metastases.Materials and methods: Liposomes were prepared by thin-film lipid hydration, followed by extrusion and the sulfate gradient-encapsulation method. Liposomes were characterized by average diameter, ζ-potential, encapsulation percentage, X-ray diffraction, and differential scanning calorimetry. Release studies in buffer (pH 7.4 or 5), plasma, and serum, as well as hydroxyapatite-affinity in vitro analysis were performed. Cytotoxicity was evaluated by MTT assay against the MDA-MB-231 cell line, and biodistribution was assessed in bone metastasis-bearing animals.Results: Liposomes presented suitable diameter (~170 nm), DOX encapsulation (~2 mg/mL), controlled release, and good plasma and serum stability. The existence of interactions between DOX and the lipid bilayer was proved through differential scanning calorimetry and small-angle X-ray scattering. DOX release was faster when the pH was in the range of a tumor than at physiological pH. The bone-targeted formulation showed a strong affinity for hydroxyapatite. The encapsulation of DOX did not interfere in its intrinsic cytotoxicity against the MDA-MB-231 cell line. Biodistribution studies demonstrated high affinity of this formulation for tumors and reduction of uptake in the heart.Conclusion: These results suggest that bone-targeted pH-sensitive liposomes containing DOX can be an interesting strategy for selectively delivering this drug into bone-tumor sites, increasing its activity, and reducing DOX-related toxicity. Keywords: hydroxyapatite-targeted formulations, bisphosphonates, pH-responsive nanostructures, bone-tumor treatment

Juliane S Lanza,1 Flaviana R Fernandes,1 José D Corrêa-Júnior,2 José MC Vilela,3 Rogério Magalhães-Paniago,4 Lucas AM Ferreira,5 Margareth S Andrade,3 Cynthia Demicheli,6 Maria N Melo,7 Frédéric Frézard1 1Department of Physiology and Biophysics, 2Department of Morphology, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), 3Innovation and Technology Center SENAI FIEMG – Campus CETEC, 4Department of Physics, Instituto de Ciências Exatas (ICEX), 5Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais (UFMG), 6Department of Chemistry, Instituto de Ciências Exatas (ICEX), 7Department of Parasitology, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil Abstract: There is a great need for orally active drugs for the treatment of the neglected tropical disease leishmaniasis. Amphiphilic Sb(V) complexes, such as 1:3 Sb–N-octanoyl-N-methylglucamide complex (SbL8), are promising drug candidates. It has been previously reported that SbL8 forms kinetically stabilized nanoassemblies in water and that this simple dispersion exhibits antileishmanial activity when given by oral route to a murine model of visceral leishmaniasis. The main objective of the present work was to interfere in the structural organization of these nanoassemblies so as to investigate their influence on the oral bioavailability of Sb, and ultimately, optimize an oral formulation of SbL8 for the treatment of cutaneous leishmaniasis. The structural organization of SbL8 nanoassemblies was manipulated through addition of propylene glycol (PG) to the aqueous dispersion of SbL8. The presence of 50% (v/v) PG resulted in the loss of hydrophobic microenvironment, as evidenced by fluorescence probing. However, nanostructures were still present, as demonstrated by dynamic light scattering, small-angle X-ray scattering, and atomic force microscopy (AFM). A remarkable property of these nanoassemblies, as revealed by AFM analysis, is the flexibility of their supramolecular organization, which showed changes as a function of the solvent and substrate polarities. The formulation of SbL8 in 1:1 water:PG given orally to mice promoted significantly higher and more sustained serum levels of Sb, when compared to SbL8 in water. The new formulation, when given as repeated doses (200 mg Sb/kg/day) to BALB/c mice infected with Leishmania amazonensis, was significantly more effective in reducing the lesion parasite burden, compared to SbL8 in water, and even, the conventional drug Glucantime® given intraperitoneally at the same dose. In conclusion, this work introduces a new concept of polarity-sensitive nanocarrier that was successfully applied to optimize an oral formulation of Sb(V) for treating cutaneous leishmaniasis. Keywords: propylene glycol, antimony, Leishmania amazonensis, AFM, amphiphilic complex, SAXS

An in situ combination of atomic force microscopy and micro x-ray diffraction was developed to study the elastic behavior of nanosized objects. This technique offers the means to locally access the Young elastic moduli and Poisson ratios of individual nanostructures. Here, we investigated the elastic behavior of a single self-assembled 450 nm high SiGe island. As pressure was applied on the island, the resonance frequency of the atomic force microscope tuning fork was tracked together with the x-ray diffraction stemming from this individual crystal. The change in the tip-island contact stiffness could be derived from the variation in the resonance frequency of the tuning fork, whereas the island mean lattice parameter was inferred from the center of mass of the island’s Bragg scattering. From this information, the reduced elastic modulus of the tip-island system could be directly determined, which is in very good agreement with literature values. The pressure needed to compress the island lattice to the Si value amounts to about 3 GPa and is in good accordance with finite-element method simulations of the displacement field in the pressurized object. [ABSTRACT FROM AUTHOR]

We investigated structural and optical properties of type-II InP/GaAs quantum dots using reflection high energy electron diffraction, transmission electron microscopy, atomic force microscopy, grazing incidence x-ray diffraction, and photoluminescence techniques. The InP dots present an efficient optical emission even when they are uncapped, which is attributed to the low surface recombination velocity in InP. We compare the difference in the optical properties between surface free dots, which are not covered by any material, with dots covered by a GaAs capping layer. We observed a bimodal dispersion of the dot size distribution, giving rise to two distinct emission bands. The results also revealed that the strain accumulated in the InP islands is slightly relieved for samples with large InP amounts. An unexpected result is the relatively large blue shift of the emission band from uncapped samples as compared to capped dots. [ABSTRACT FROM AUTHOR]

Si islands were grown on Ge (111) in Volmer-Weber growth mode with a 40-nm thick Ge0.85Si0.15 buffer. The state of strain and chemical composition of these islands were evaluate by grazing incidence anomalous x-ray diffraction. The results show evidence of lattice coherence and Ge-Si intermixing. A direct relationship between increase in substrate temperature and enhancement of alloying was found, evidencing the importance of atomic interdiffusion in this growth mode. [ABSTRACT FROM AUTHOR]