Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexylcyanoacrylate nanoparticles

Abstract

Doxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 mg/m2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/m2 and the recommended phase II dose was 75 mg/m2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60, 60 and 75 mg/m2) and was compared with free DXR given to the same patients in the same conditions.

Drug transport to brain with targeted nanoparticles

“…17 Lacking stealth properties, poly(alkylcyanoacrylate) nanoparticles administered intravenously are rapidly cleared from the blood stream by the monuclear phagocyte system (MPS) and mainly accumulate in liver and spleen, 18 -20 together with the entrapped compounds. [21][22][23] Only pegylated polyalkylcyanoacrylate nanoparticles have lower MPS uptake and prolonged blood circulation in vivo.…”

Cellular Interactions of Nano Drug Delivery Systems

“…Cancer therapy for instance is severely limited by the toxicity caused by the antitumor agents on normal cells. Doxorubicin treatment is associated with severe cardiotoxicity and hepatotoxicity, but when it was administered using nanoparticles, neither of theses side effects were observed due to the localization of the nanoparticle formulation to the tumor (Kattan et al, 1992). It is critical that the drug delivery vehicle does not upset the normal physiology of the biological system, while exploiting the unique pathophysiological characteristics of diseased tissue or cell.…”

Orthogonal Transformations on Solid Substrates: Efficient Avenues to Surface Modification

“…[148,149] Clinical trials have even shown that these nanodevices are safe and biocompatible when loaded with the anticancer drug doxorubicin. [150] Nicolas et al [151] proposed a general methodology to prepare highly functionalized PACA nanoparticles by means of Huisgen 1,3-dipolar cycloaddition. To achieve this goal, different protocols were investigated to obtain azido PEG cyanoacrylate of variable molar mass, followed by a Knoevenagel condensation-Michael addition reaction with hexadecyl cyanoacrylate to produce a poly[(hexadecyl cyanoacrylate)-co-azido poly(ethylene glycol) cyanoacrylate] [P(HDCA-co-N 3 PEGCA)] copolymer, displaying azide functionalities at the extremity of the PEG chains.…”