Transcriptional responses of human aortic endothelial cells to nanoconstructs used in biomedical applications.

Understanding the potential toxicities of manufactured nanoconstructs used for drug delivery and biomedical applications may help improve their safety. We sought to determine if surface-modified silica nanoparticles and poly(amido amine) dendrimers elicit genotoxic responses on vascular endothelial cells. The nanoconstructs utilized in this study had a distinct geometry (spheres vs worms) and surface charge, which were used to evaluate the contributions of these parameters to any potential adverse effects of these materials.

Biological evaluation of RGDfK-gold nanorod conjugates for prostate cancer treatment.

Selective delivery of gold nanorods (GNRs) to sites of prostate tumor angiogenesis is potentially advantageous for localized photothermal therapy. Here, we report the cellular uptake and biodistribution of GNRs surface functionalized with the cyclic RGDfK peptide. The GNRs were synthesized to have a surface plasmon resonance (SPR) peak at 800?nm and grafted with a thiolated poly(ethylene glycol) (PEG) corona with or without RGDfK.

Impact of silica nanoparticle design on cellular toxicity and hemolytic activity.

Understanding the toxicity of silica nanoparticles (SiO(2)) on the cellular level is crucial for rational design of these nanomaterials for biomedical applications. Herein, we explore the impacts of geometry, porosity, and surface charge of SiO(2) on cellular toxicity and hemolytic activity. Nonporous Stöber silica nanospheres (115 nm diameter), mesoporous silica nanospheres (120 nm diameter, aspect ratio 1), mesoporous silica nanorods with aspect ratio of 2, 4, and 8 (width by length 80 × 200 nm, 150 × 600 nm, 130 × 1000 nm), and their cationic counterparts were evaluated on macrophages, lung carcinoma cells, and human erythrocytes.

Comparison of active and passive targeting of docetaxel for prostate cancer therapy by HPMA copolymer-RGDfK conjugates.

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel-RGDfK conjugate was synthesized, characterized, and evaluated in vitro and in vivo in comparison with untargeted low and high molecular weight HPMA copolymer-docetaxel conjugates. The targeted conjugate was designed to have a hydrodynamic diameter below renal threshold to allow elimination post treatment. All conjugates demonstrated the ability to inhibit the growth of DU145 and PC3 human prostate cancer cells and the HUVEC at low nanomolar concentrations.

Silica nanoconstruct cellular toleration threshold in vitro.

The influence of geometry of silica nanomaterials on cellular uptake and toxicity on epithelial and phagocytic cells was studied. Three types of amine-terminated silica nanomaterials were prepared and characterized via the modified Stober method, namely spheres (178±27 nm), worms (232±22 nm×1348±314 nm) and cylinders (214±29 nm×428±66 nm). The findings of the study suggest that in this size range and for the cell types studied, geometry does not play a dominant role in the modes of toxicity and uptake of these particles.

Anticancer and antiangiogenic activity of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer therapy.

Tumor progression is dependent on neoangiogenesis for blood supply. Neovasculature over-express α(v)β(3) integrins which recognize the Arg-Gly-Asp (RGD) sequence in the extracellular matrix. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing side chains terminated in cyclic RGD analogs such as RGDfK show increased accumulation in prostate tumors.

HPMA copolymer-aminohexylgeldanamycin conjugates targeting cell surface expressed GRP78 in prostate cancer.

Purpose: This study focused on the synthesis and in vitro characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates for the delivery of geldanamycin to prostate cancer tumors. Conjugates were modified to incorporate WIFPWIQL peptide, which binds to cell-surface-expressed Glucose-regulated protein 78.

Methods: HPMA copolymers containing aminohexylgeldanamycin with and without WIFPWIQL peptide were synthesized and characterized, and stability in pH 7.

Carboxyl-terminated PAMAM-SN38 conjugates: synthesis, characterization, and in vitro evaluation.

In this work, carboxyl-terminated PAMAM G-3.5 was covalently attached to SN38 via glycine and β-alanine spacers. The conjugates were stable at pH 7.

PAMAM-camptothecin conjugate inhibits proliferation and induces nuclear fragmentation in colorectal carcinoma cells.

Purpose: To synthesize and characterize a poly (amido amine) dendrimer-camptothecin (PAMAM-CPT) conjugate and evaluate its activity on human colorectal carcinoma cells (HCT-116).

Methods: The attachment of CPT to amine-terminated PAMAM was facilitated through a succinic acid-glycine linker. The conjugate was characterized for absence of small molecular weight impurities, size and drug content.

Cellular uptake and toxicity of gold nanoparticles in prostate cancer cells: a comparative study of rods and spheres.

Using a series of gold nanoparticles with incremental increase in dimensions but varying geometries (spherical vs rods) we have evaluated the influence of shape, size, surface properties and concentration on cellular uptake, adsorption of proteins and toxicity in a human prostate cancer cell line (PC-3). In the range of 30-90 nm diameter studied, spherical particles of 50 nm in diameter without polyethylene glycol (PEG) had the highest uptake. Surface attachment of PEG reduced cellular uptake.

HPMA copolymer-bound doxorubicin induces apoptosis in ovarian carcinoma cells by the disruption of mitochondrial function.

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-bound doxorubicin has showed greater potency than free doxorubicin in the treatment of ovarian cancer in vivo and in vitro. The promising activity of the conjugate demonstrated in clinical trials has generated considerable interest in understanding the mechanism of action of this macromolecular therapeutic. In this study, the involvement of the mitochondrial pathway in HPMA copolymer-bound doxorubicin-induced apoptosis in the human ovarian cancer cell line A2780 was investigated.

HPMA copolymer-bound doxorubicin induces apoptosis in human ovarian carcinoma cells by a Fas-independent pathway.

The mechanism of cell death in A2780 human ovarian carcinoma cells induced by free doxorubicin (DOX) and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound DOX [P-(GFLG)-DOX] was investigated. In particular, the involvement of the Fas receptor system in drug-induced apoptosis was evaluated. P-(GFLG)-DOX was shown to effect apoptosis-induced tumor cell death as manifested by positive Annexin V-FITC staining, cleavage of procaspase 3 and its physiological substrate, poly(ADP-ribose) polymerase (PARP), and cleavage of procaspase 8.

Free and N-(2-hydroxypropyl)methacrylamide copolymer-bound geldanamycin derivative induce different stress responses in A2780 human ovarian carcinoma cells.

The effects of geldanamycin (GA), 17-(3-aminopropylamino)-17-demethoxygeldanamycin (AP-GA), and N-(2-hydroxypropyl)methacrylamide copolymer-AP-GA conjugate [P(AP-GA)] on A2780 human ovarian carcinoma cells at an equitoxic dose (2x IC(50)) were compared by the gene expression array analysis. All treatments resulted in similar gene expression profiles up to 12 h (e.g.