Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality.

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This paper introduces the unnatural amino acid Abc 2K as a nanometer-length building block for the creation of water-soluble molecular rods of exceptional size. Abc 2K is a water-soluble variant of the unnatural amino acid 4'-amino-[1,1'-biphenyl]-4-carboxylic acid (Abc) with lysinelike propyloxyammonium side chains at the 2-and 5-positions. The protected building block Fmoc-Abc 2K(Boc)-OH (1) can be used in standard Fmoc-based solid-phase peptide synthesis to create watersoluble rodlike peptides in nanometer unit lengths up to at least ten nanometers. Oligomers up to and including the decamer were easily prepared on a Rink amide resin. These peptides are easy to purify and characterize by standard reverse-phase HPLC, 1 H NMR, and ESI-MS techniques. The Abc 2K amino acid can be combined with various standard amino acids to provide well behaved hybrid and biologically relevant peptides. Building block 1 is efficiently prepared on a multigram scale from commercially available starting materials by way of the Suzuki cross-coupling reaction. Molecular modeling studies of Abc 2K oligomers show only minor effects from torsional and bending motions and support a model in which the oligomers are relatively straight and rigid. Fluorescence resonance energy transfer (FRET) studies are consistent with a model in which the Abc 2K oligomers behave as rigid rods with a length of 1.0 nm per monomer unit. This paper introduces the unnatural amino acid Abc 2K as a nanometer-length building block for the creation of water-soluble molecular rods in nanometer unit lengths up to at least ten nanometers. Over the past two decades, molecular rods have been developed that can be assembled in precise constitution and length from individual building blocks. 1-4 Many of these oligomers, such as staffanes and oligo(p-phenylene ethynylene)s, require carbon-carbon bond formation for their synthesis and are designed to be soluble in organic solvents. 1 Nucleic acids provide one attractive approach to water-soluble oligomers and have been used as rodlike components in a variety of architectures. 2 Peptides and peptide derivatives provide a particularly attractive approach, both because of their biological compatibility and relevance, and because of their ease of assembly through widely available peptide synthesis technologies. 3 Here, we introduce water-soluble rodlike peptides of exceptional size that are constructed from a 1.0-nm long θ-amino acid. These θ-peptides are easy to assemble and purify with standard peptide synthesis and purification technologies and can be combined with biologically relevant peptides.