Carboxylesterase-triggered hydrolysis of nanoparticle PEGylating agents.

Despite the importance of PEGylation in achieving long nanoparticle circulation times, many nanoparticles are coated with PEGylating agents susceptible to enzymatic degradation. In this study, solid lipid nanoparticles (SLNs) prepared with ester-containing compounds were evaluated for their stability in the presence of carboxylesterase. SLN suspensions became turbid within 30 min of enzymatic exposure, indicating possible disassociation of a portion of the nanoparticles.

Physicochemical characterization of nanotemplate engineered solid lipid nanoparticles.

As the physicochemical characteristics of solid lipid nanoparticles (SLNs) play a critical role in their success, it is important to understand how the materials and process used in their preparation affect these properties. In this study, two stearyl alcohol-based formulations were prepared using nanotemplate engineering technology and characterized. Both formulations were of a small particle size (<100 nm), ellipsoidal shape, and low polydispersity.

Uniformity of drug payload and its effect on stability of solid lipid nanoparticles containing an ester prodrug.

Nanocarrier systems are frequently characterized by their size distribution, while drug encapsulation in nanocarriers is generally characterized in terms of an entire population, assuming that drug distribution is uniform. Careful characterization of nanocarriers and assessment of their behavior in biological environments are essential for adequate prediction of the fate of the nanoparticles in vivo. Solid lipid nanoparticles containing [(3)H]-dexamethasone palmitate (an ester prodrug) and [(14)C]-stearyl alcohol (a component of the nanoparticle matrix) were prepared using the nanotemplate engineering method for bioresponsive tumor delivery to overcome interstitial fluid pressure gradients, a physiological barrier to tumor uptake of chemotherapeutic agents.

Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers.

Purpose: To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor in advanced cancer patients.

Experimental Design: Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated.

A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies.

Purpose: 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v.

Nanoparticles containing anti-inflammatory agents as chemotherapy adjuvants: optimization and in vitro characterization.

The pre-administration of dexamethasone (DEX) has previously been shown to enhance the anti-tumor efficacy of chemotherapeutic agents. The delivery of anti-inflammatory agents specifically to tumors via nanoparticle carriers is expected to promote the effectiveness of chemotherapeutic agents while avoiding systemic toxicities. The process for preparing solid lipid nanoparticles containing anti-inflammatory agents using the nanotemplate engineering method was optimized.

Dexamethasone as a chemosensitizer for breast cancer chemotherapy: potentiation of the antitumor activity of adriamycin, modulation of cytokine expression, and pharmacokinetics.

Dexamethasone (DEX) is mainly used as an anti-emetic agent in cancer therapy. We have recently demonstrated that DEX pretreatment increases the antitumor activity of the cancer chemotherapeutic agents carboplatin and gemcitabine, and decreases host toxicity in nude mouse xenograft models of human cancer. However, the underlying mechanisms are not fully understood.

Effect of docetaxel chemotherapy on the activity of a gonadotropin releasing hormone vaccine in patients with advanced prostate cancer.

Background: Gonadotropin releasing hormone (GnRH)-DT vaccine elicits antibody that may inhibit prostate cancers indirectly by blocking GnRH induced gonadotropin release, and consequent androgen synthesis, and directly by immune effector and antiproliferative mechanisms. A pilot study was performed to determine how to best combine GnRH-DT vaccine with potentially immunosuppressive chemotherapy.

Methods: Patients with metastatic, hormone-refractory prostate cancer were randomized into either a concurrent cohort, in which they received docetaxel on day 1 of weeks 1, 4, 7, and 10 and GnRH-DT vaccine on day 2 of weeks 1, 3, and 7 or a sequential cohort, in which they received GnRH-DT vaccine on weeks 1, 3, and 7 before beginning docetaxel on week 10.

Pretreatment with dexamethasone increases antitumor activity of carboplatin and gemcitabine in mice bearing human cancer xenografts: in vivo activity, pharmacokinetics, and clinical implications for cancer chemotherapy.

Purpose: The present study was undertaken to determine the effects of dexamethasone (DEX) pretreatment on antitumor activity and pharmacokinetics of the cancer chemotherapeutic agents carboplatin and gemcitabine.

Experimental Design: Antitumor activities of carboplatin and gemcitabine with or without DEX pretreatment were determined in six murine-human cancer xenograft models, including cancers of colon (LS174T), lung (A549 and H1299), and breast (MCF-7 and MDA-MB-468) and glioma (U87-MG). Effects of DEX on plasma and tissue pharmacokinetics of carboplatin and gemcitabine were also determined by using the LS174T, A549, and H1299 models.

Dexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine.

Purpose: Hematoprotective strategies may offer new approaches to prevent chemotherapy-induced hematotoxicity. The present study was undertaken to investigate the chemoprotective effects of dexamethasone and its optimal dose and the underlying mechanisms.

Methods: Lethal toxicity and hematotoxicity of carboplatin were compared in CD-1 mice with or without dexamethasone pretreatment.