We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.

A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.

The three most common methods of sterilization in use today are ethylene oxide exposure, ␥-irradiation, and steam sterilization. Each of these methods has serious limitations for the sterilization of some materials used in medicine, especially thermally and hydrolytically sensitive polymers by themselves and in combination with proteins. In this work, we demonstrate a potential new method of sterilization by using supercritical f luid carbon dioxide. Using this method we achieve complete inactivation of a wide variety of bacterial organisms at moderate temperatures and in the absence of organic solvents or irradiation. Sterilization is a function of both the proximity to the f luid's critical point and the chemical nature of the f luid itself. When biodegradable polymers poly(lactic-co-glycolic) acid and polylactic acid were included in the sterilization process, there was no effect on the inactivation efficiency, yet no physical or chemical damage to these thermally and hydrolytically labile materials was observed.

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The design of biomaterials containing specific ligands on the surface offers the possibility of creating materials that can interact with and potentially control mammalian cell behavior. Biodegradable materials further provide the significant advantage that the polymer will disappear in vivo, obviating long-term negative tissue responses as well as the need for retrieval. In earlier studies we synthesized and characterized arginine-glycine-aspartic acid (RGD) peptide-modified poly(lactic acid-co-lysine) (PLAL). In this study, both bulk properties and surface features have been characterized, with a focus on surface analysis as a means of interpreting observed changes in cell behavior. Bulk peptide attachments were performed using 1,1Ј-carbonyldiimidazole (CDI). Amino groups were measured using colorimetric assays and X-ray photoelectron spectroscopy (XPS). Peptides were measured by incorporating iodine into the peptide as a distinct elemental marker for use with XPS. Typical samples contained 13 ± 4 pmol/cm 2 of amino groups and 4 ± 0.2 pmol/ cm 2 of peptides, as calculated from XPS measurements of nitrogen and iodine. The wettability and crystallinity of the samples were determined by contact angles and differential scanning calorimetry, respectively. Wettability and crystallinity were not altered by the incorporation of lysine or peptides. After incubating bovine aortic endothelial (BAE) cells for 4 h on surfaces with RGD-containing peptides, the mean spread cell area increased from 77 ± 2 m 2 to 405 ± 29 m 2 compared to 116 ± 11 m 2 on poly(lactic acid), 87 ± 4 m 2 on PLAL, and 105 ± 4 m 2 on surfaces with RDG-containing (control) peptides. The significance of this work is that the first synthetic interactive, resorbable biomaterial has been developed, and use of this material to control cell behavior has been demonstrated.

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Monomodal polysilylenes with relatively narrow molecular weight distributions (MJMn < 1.5) have been prepared by the reductive coupling of methylphenyldichlorosilane and di-n-hexyldichlorosilane with alkali metals in toluene in the presence of ultrasound. The optimum conditions for the sonochemical synthesis of well-defined polysilylenes in the presence of an immersion-type probe were studied. Sonochemical synthesis is accompanied by selective degradation which decreases the molecular weight to the limiting value of Mn « 50 000 and also reduces polydispersities (MJMn < 1.2). Polymerization depends strongly on the substituents on the silicon atoms, solvents, alkali metals, and temperature. For example, the polymerization of methylphenyldichlorosilane in toluene with potassium, in contrast to that with sodium, does not produce a polysilylene because the reactivity of potassium is too high, leading to side reaction.

The design of biomaterials containing specific ligands on the surface offers the possibility of creating materials that can interact with and potentially control mammalian cell behavior. Biodegradable materials further provide the significant advantage that the polymer will disappear in vivo, obviating long-term negative tissue responses as well as the need for retrieval. In earlier studies we synthesized and characterized arginine-glycine-aspartic acid (RGD) peptide-modified poly(lactic acid-co-lysine) (PLAL). In this study, both bulk properties and surface features have been characterized, with a focus on surface analysis as a means of interpreting observed changes in cell behavior. Bulk peptide attachments were performed using 1,1'-carbonyldiimidazole (CDI). Amino groups were measured using colorimetric assays and X-ray photoelectron spectroscopy (XPS). Peptides were measured by incorporating iodine into the peptide as a distinct elemental marker for use with XPS. Typical samples contained 13 +/- 4 pmol/cm2 of amino groups and 4 +/- 0.2 pmol/ cm2 of peptides, as calculated from XPS measurements of nitrogen and iodine. The wettability and crystallinity of the samples were determined by contact angles and differential scanning calorimetry, respectively. Wettability and crystallinity were not altered by the incorporation of lysine or peptides. After incubating bovine aortic endothelial (BAE) cells for 4 h on surfaces with RGD-containing peptides, the mean spread cell area increased from 77 +/- 2 microns2 to 405 +/- 29 microns2 compared to 116 +/- 11 microns2 on poly(lactic acid), 87 +/- 4 microns2 on PLAL, and 105 +/- 4 microns2 on surfaces with RDG-containing (control) peptides. The significance of this work is that the first synthetic interactive, resorbable biomaterial has been developed, and use of this material to control cell behavior has been demonstrated.