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Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors., (Copyright 2009 Elsevier B.V. All rights reserved.)

Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) enables cancer cells to develop resistance to multiple anticancer drugs. Functional inhibitors of P-gp have shown promising efficacy in early clinical trials, but their long-term safety is yet to be established. A novel approach to overcome drug resistance is to use siRNA-mediated RNA interference to silence the expression of the efflux transporter. Because P-gp plays an important role in the physiological regulation of endogenous and xenobiotic compounds in the body, it is important to deliver P-gp targeted siRNA and anticancer drug specifically to tumor cells. Further, for optimal synergy, both the drug and siRNA may need to be temporally colocalized in the tumor cells. In the current study, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel, along with P-gp targeted siRNA, using poly(D,L-lactide-co-glycolide) nanoparticles to overcome tumor drug resistance. Nanoparticles were surface functionalized with biotin for active tumor targeting. Dual agent nanoparticles encapsulating the combination of paclitaxel and P-gp targeted siRNA showed significantly higher cytotoxicity in vitro than nanoparticles loaded with paclitaxel alone. Enhanced therapeutic efficacy of dual agent nanoparticles could be correlated with effective silencing of the MDR1 gene that encodes for P-gp and with increased accumulation of paclitaxel in drug-resistant tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and P-gp targeted siRNA at a paclitaxel dose that was ineffective in the absence of gene silencing. These results suggest that that the combination of P-gp gene silencing and cytotoxic drug delivery using targeted nanoparticles can overcome tumor drug resistance.

Targeted drug delivery using nanocarriers is achieved by functionalizing the carrier surface with a tissue-recognition ligand. Current surface modification methods require tedious and inefficient synthesis and purification steps, and are not easily amenable to incorporating multiple functionalities on a single surface. In this report, we describe a versatile, single-step surface functionalizing technique for polymeric nanoparticles. The technique utilizes the fact that when a diblock copolymer like polylactide-polyethylene glycol (PLA-PEG) is introduced in the oil/water emulsion used in polymeric nanoparticle formulation, the PLA block partitions into the polymer containing organic phase and PEG block partitions into the aqueous phase. Removal of the organic solvent results in the formation of nanoparticles with PEG on the surface. When a PLA-PEG-ligand conjugate is used instead of PLA-PEG copolymer, this technique permits a 'one-pot' fabrication of ligand-functionalized nanoparticles. In the current study, the IAASF approach facilitated the simultaneous incorporation of biotin and folic acid, known tumor-targeting ligands, on drug-loaded nanoparticles in a single step. Incorporation of the ligands on nanoparticles was confirmed by using NMR, surface plasmon resonance, transmission electron microscopy and tumor cell uptake studies. Simultaneous functionalization with both ligands significantly enhanced nanoparticle accumulation in tumors in vivo, and resulted in greatly improved efficacy of paclitaxel-loaded nanoparticles in a mouse xenograft tumor model. This new surface functionalization approach will enable the development of targeting strategies based on the use of multiple ligands on a single surface to target a tissue of interest.

The tribological behavior of traditional oil-in-water (O/W) lubricants (1.0 wt.%) and nano-TiO2 additive lubricants (1.0–9.0 wt.%) during micro rolling of titanium foils were analyzed. In this study, the surface morphologies of titanium foils under various lubrication conditions were assessed, and the corresponding lubrication mechanisms were revealed. The tribological behavior of nano-TiO2 additive lubricants during micro rolling of titanium foils was also explored through a series of characterization methods. The utilization of nano-TiO2 additive lubricants in micro rolling reduces the surface roughness of titanium foils. Moreover, it effectively inhibits the generation of indentations and cracks during rolling processes, enhancing the surface quality of rolled specimens. Additionally, owing to the synergism of rolling, tribo-film, mending and polishing effects of the nanoparticles, both the rolling force and surface roughness were minimized by using lubricants containing 3.0 wt.% TiO2 nanoparticles. Overall, an optimal concentration (3.0 wt.%) of TiO2 nanoparticles in water-based nanolubricants was obtained with enhanced tribological properties and lubrication performance during micro rolling of titanium foils. [ABSTRACT FROM AUTHOR]

In this work, an experimental investigation on the lubrication performance of water-based nanolubricant with TiO2 as nanoadditives was performed. The nanolubricants show excellent dispersibility and stability within 5 days after preparation. Additionally, the results show that the concentration of TiO2 nanoparticles significantly affects the lubrication performance of the prepared nanolubricant during microrolling. The excessive nanoparticles lead to agglomeration at the contact area, while the limited nanoparticles can hardly work during rolling processes. Instead, for a nanolubricant with 3.0 wt% of TiO2 nanoparticles, the nanolubricant is able to feed abundant nanoparticles continuously to the rubbing zone with little agglomeration, improving the surface quality of copper foils during microrolling. [ABSTRACT FROM AUTHOR]