In this work we describe the formulation and characterization of chemically modified polymeric nanocapsules incorporating the anticancer drug, quercetin, for the passive and active targeting to tumors. Folic acid was conjugated to poly(lactide-co-glycolide) (PLGA) polymer to facilitate active targeting to cancer cells. Two different methods for the conjugation of PLGA to folic acid were employed utilizing polyethylene glycol (PEG) as a spacer. Characterization of the conjugates was performed using FTIR and (1)H NMR studies. The PEG and folic acid content was independent of the conjugation methodology employed. PEGylation has shown to reduce the size of the nanocapsule; moreover, zeta-potential was shown to be polymer-type dependent. Comparative studies on the cytotoxicity and cellular uptake of the different formulations by HeLa cells, in the presence and absence of excess folic acid, were carried out using MTT assay and Confocal Laser Scanning Microscopy, respectively. Both results confirmed the selective uptake and cytotoxicity of the folic acid targeted nanocapsules to the folate enriched cancer cells in a folate-dependent manner. Finally, the passive tumor accumulation and the active targeting of the nanocapsules to folate-expressing cells were confirmed upon intravenous administration in HeLa or IGROV-1 tumor-bearing mice. The developed nanocapsules provide a system for targeted delivery of a range of hydrophobic anticancer drugs in vivo.

Carbon nanotubes (CNTs) are a novel nanocarriers with interesting physical and chemical properties. Here we investigate the ability of amino-functionalized multi-walled carbon nanotubes (MWNTs-NH3+) to cross the Blood-Brain Barrier (BBB) in vitro using a co-culture BBB model comprising primary porcine brain endothelial cells (PBEC) and primary rat astrocytes, and in vivo following a systemic administration of radiolabelled f-MWNTs. Transmission Electron microscopy (TEM) confirmed that MWNTs-NH3+ crossed the PBEC monolayer via energy-dependent transcytosis. MWNTs-NH3+ were observed within endocytic vesicles and multi-vesicular bodies after 4 and 24 h. A complete crossing of the in vitro BBB model was observed after 48 h, which was further confirmed by the presence of MWNTs-NH3+ within the astrocytes. MWNT-NH3+ that crossed the PBEC layer was quantitatively assessed using radioactive tracers. A maximum transport of 13.0 ± 1.1% after 72 h was achieved using the co-culture model. f-MWNT exhibited significant brain uptake (1.1  ±  0.3% injected dose/g) at 5 min after intravenous injection in mice, after whole body perfusion with heparinized saline. Capillary depletion confirmed presence of f-MWNT in both brain capillaries and parenchyma fractions. These results could pave the way for use of CNTs as nanocarriers for delivery of drugs and biologics to the brain, after systemic administration.

Clinical applications of curcumin for the treatment of cancer and other chronic diseases have been mainly hindered by its short biological half-life and poor water solubility. Nanotechnology-based drug delivery systems have the potential to enhance the efficacy of poorly soluble drugs for systemic delivery. This study proposes the use of poly(lactic-co-glycolic acid) (PLGA)-based polymeric oil-cored nanocapsules (NCs) for curcumin loading and delivery to colon cancer in mice after systemic injection. Formulations of different oil compositions are prepared and characterized for their curcumin loading, physico-chemical properties, and shelf-life stability. The results indicate that castor oil-cored PLGA-based NC achieves high drug loading efficiency (≈18% w(drug)/w(polymer)%) compared to previously reported NCs. Curcumin-loaded NCs internalize more efficiently in CT26 cells than the free drug, and exert therapeutic activity in vitro, leading to apoptosis and blocking the cell cycle. In addition, the formulated NC exhibits an extended blood circulation profile compared to the non-PEGylated NC, and accumulates in the subcutaneous CT26-tumors in mice, after systemic administration. The results are confirmed by optical and single photon emission computed tomography/computed tomography (SPECT/CT) imaging. In vivo growth delay studies are performed, and significantly smaller tumor volumes are achieved compared to empty NC injected animals. This study shows the great potential of the formulated NC for treating colon cancer.

Graphene nanoplatelets (GNP) were exfoliated using a nondestructive chemical reduction method and subsequently decorated with polymers using two different approaches: graf ting f rom and graf ting to. Poly(methyl methacrylate) (PMMA) with varying molecular weights was covalently attached to the GNP layers using both methods. The grafting ratios were higher (44.6% to 126.5%) for the graf ting f rom approach compared to the grafting to approach (12.6% to 20.3%). The products were characterized using thermogravimetric analysis−mass spectrometry (TGA-MS), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), atomic force microscopy (AFM), and transmission electron microscopy (TEM). The graf ting f rom products showed an increase in the grafting ratio and dispersibility in acetone with increasing monomer supply; on the other hand, due to steric effects, the graf ting to products showed lower absolute grafting ratios and a decreasing trend with increasing polymer molecular weight. The excellent dispersibility of the grafting f rom functionalized graphene, 900 μg/mL in acetone, indicates an increased compatibility with the solvent and the potential to increase graphene reinforcement performance in nanocomposite applications.

We report in this study the complexation of the chemotherapeutic drug doxorubicin (DOX) with the novel sixth-generation cationic poly-l-lysine dendrimer (DM) (MW 8149 kDa), which we previously reported to exhibit systemic antiangiogenic activity in tumor-bearing mice. DOX-DM complexation was confirmed by florescence polarization measurement, proton nuclear magnetic resonance spectroscopy, and molecular modeling. Enhanced penetration of DOX-DM (at 1:10 molar ratio), compared to the free DOX, into prostate 3D multicellular tumor spheroids (MTS) was confirmed by confocal laser scanning microscopy. Furthermore, DOX-DM complexes achieved a significantly higher cytotoxicity in DU145 MTS system compared to the free drug, as shown by growth delay curves. Incubation of MTS with low DOX concentration (1 μM) complexed with DM led to a significant delay in MTS growth compared to untreated MTS or MTS treated with free DOX. DOX-DM complex retention was also achieved in a Calu-6 lung cancer xenograft model in tumor-bearing mice, as shown by live whole animal fluorescence imaging. Therapeutic experiments in B16F10 tumor bearing mice have shown enhanced therapeutic efficacy of DOX when complexed to DM. This study suggests that the cationic poly-l-lysine DM molecules studied here could, in addition to their systemic antiangiogenic property, complex chemotherapeutic drugs such as DOX and improve their accumulation and cytotoxicity into MTS and solid tumors in vivo. Such an approach offers new capabilities for the design of combinatory antiangiogenic/anticancer therapeutics.