In the attempt to develop novel concepts in designing targeted nanoparticles for combination therapy of cancer, we propose here CD44-targeted hyaluronan-decorated double-coated nanoparticles (dcNPs) delivering the lipophilic chemotherapeutic docetaxel (DTX) and an anionic porphyrin (TPPS₄). dcNPs are based on electrostatic interactions between a negative DTX-loaded nanoscaffold of poly(lactide-co-glycolide), a polycationic shell of polyethyleneimine entangling negatively-charged TPPS₄ and finally decorated with hyaluronan (HA) to promote internalization through CD44 receptor-mediated endocytosis. DTX/TPPS₄-dcNPs, prepared through layer-by-layer deposition, showed a hydrodynamic diameter of around 180 nm, negative zeta potential and efficient loading of both DTX and TPPS₄. DTX/TPPS₄-dcNPs were freeze-dried with trehalose giving a powder that could be easily dispersed in different media. Excellent stability of dcNPs in specific salt- and protein-containing media was found. Spectroscopic behavior of DTX/TPPS₄-dcNPs demonstrated a face-to-face arrangement of the TPPS₄ units in non-photoresponsive H-type aggregates accounting for an extensive aggregation of the porphyrin embedded in the shell. Experiments in MDA-MB-231 cells overexpressing the CD44 receptor demonstrated a 9.4-fold increase in the intracellular level of TPPS₄ delivered from dcNPs as compared to free TPPS₄. Light-induced death increased tremendously in cells that had been treated with a combination of TPPS₄ and DTX delivered through dcNPs as compared with free drugs, presumably due to efficient uptake and co-localization inside the cells. In perspective, the strategy proposed here to target synergistic drug combinations through HA-decorated nanoparticles seems very attractive to improve the specificity and efficacy of cancer treatment.

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The photophysical properties of rufloxacin, 9‐fluoro‐2r3‐dihydro‐10‐(4‐methyl‐l‐pyrazinyl)‐7‐oxo‐7‐H‐pyri‐do[l,2,3‐de]‐l,4‐benzothiazin‐6‐carboxylic acid, a fluoroquinolone antibacterial drug exhibiting photosensitizing action toward biological substrates, were studied in aqueous solutions at neutral pH. The lowest excited electronic states of the zwitterion were characterized by both experimental techniques and theoretical methods. Steady‐state and time‐resolved emission, triplet‐state absorption and singlet oxygen production were investigated. The results indicate that the lowest excited singlet is a fluorescent, relatively long‐lived state (φr= 0.075, Tr≅ 4.5 ns) with an efficient intersystem crossing to the triplet manifold (φisc≅ 0‐7)‐ The lowest triplet is a long‐lived state (TT≅ 10 μs at 295 K in 0.01 M phosphate buffer), with properties that make it a good candidate for being the precursor of the photodecarboxylation of the drug. It is quenched by oxygen at a rate of 1.7 times 109M‐1 s‐1 and singlet oxygen is formed with a quantum yield of 0.32 in air‐saturated solutions.

The photosensitizing activity of enoxacin, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)- 1,8-naphthyridine-3-carboxilic acid (ENX), toward membranes and DNA has been studied, taking into account human erythrocyte photohemolysis, unilamellar liposome alterations and plasmid pBR322 DNA photocleavage. Hydroxyl radicals and an aromatic carbene generated from ENX photodefluorination seem to be the active intermediates involved in the photosensitization process. The steady-state photolysis products do not participate in the process. The mechanism of photosensitization responsible for the membrane damage depends on the oxygen concentration and follows a different path with respect to that operative for DNA cleavage. Between oxygenated radicals, the hydroxyl seems the species mainly responsible for membrane damage, whereas DNA cleavage is mainly produced by the carbene intermediate. A molecular mechanism of the photosensitization induced by ENX is proposed.

Several in vitro and in vivo studies have suggested that carnosine can act as a scavenger of reactive oxygen species and intracellular proton buffer. On the other hand, carnosinase is a specific peptidase able to destroy the biological active dipeptide. To overcome this constraint, b-cyclodextrin (b-CD) was functionalized with carnosine to give the following new compounds:. Pulse-radiolysis investigation showed that the b-CD derivatives 1 ± 3 are excellent scavengers of OH . radicals. Their activity is not only due to the formation of the stable imidazole-centered radical, but also to the scavenger ability of the glucose moieties of the macrocycle (Scheme). This effect is independent of the disposition of the imidazole ring. In fact, the quenching constant values are similar for the three compounds.Introduction. ± Cyclodextrins (CDs), cyclic oligomers of a-d-glucopyranose, have attracted interest in a variety of contexts [1 ± 7], which include studies of their role in the realization of delivery systems [6 ± 12]. This is also reflected in the increasing number of patents in this field. Drug targeting commonly involves the use of cyclomaltosaccharides as CD inclusion complexes [7 ± 13]. It has been pointed out that the use of CD as a drug carrier may sometimes provide a simple, cheap, and effective strategy to increase drug solubility [6] [7] [12] [13], stability [6] [7] [12] [13], and photostability [14 ± 16] to modulate drug photoreactivity as well as to minimize the photoinduced toxic effects of a drug on biosubstrates [17] [18]. The bio-availability and effectiveness of the drug itself [6] [7] [12] may also be improved, especially in the case of lipophilic drugs. Cyclodextrin complexation has proved promising in stabilizing and increasing the absorption of growth hormones [19], interleukin-2 [19], aspartame [20], albumine [21], g-globuline [21], cyclosporine A [22], calcitonin [23], and insulin [6] [24] [25]. Rapid plasma clearance and problems regarding immunogenicity [6 ± 8] may limit the practical use of peptides or proteins of therapeutic importance. The covalent linkage of bioactive peptides to cyclodextrins has recently been proposed as a means of achieving good results in terms of solubility and reduced catabolism [26 ± 35]. The data reported support an interest in developing the design and investigation of such molecules. Biological peptides such as enkephalin [26] [31], enkephalin analogue DPDPE [33], neuropeptide substance P [30], and gastrin peptides [27] have been grafted onto CDs.