Polymeric Nanoparticles

Abraxane™ is the only example of a regulatory approved (FDA, USA) nanoparticle formulation for intravenous drug delivery in cancer patients. It is paclitaxel bound to albumin nanoparticles, with a mean diameter of 130 nm, for use in individuals with metastatic breast cancer who have failed combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. This formulation overcomes poor solubility of paclitaxel in the blood and allows patients to receive 50% more paclitaxel per dose over a 30-min period.26,27 Unlike Cremophor® EL/ethanol or Tween® 80-solubilized taxanes, acute hypersensitivity reactions, which are secondary to complement activation, have yet to be reported following Abraxane™ infusion. Albumin nanoparticles seem to interact with gp60 receptors present on tumor blood vessels that transport the nanoparticles into tumor interstitial spaces by transcytosis, a process that may partly contribute to the effectiveness of Abraxane™. However, hepatic deposition (Kupffer cell capture) and processing of a significant fraction of albumin nanoparticles are most likely to occur. Indeed, after a 30 min infusion of 260 mg/m2 doses of Abraxane™, faecal excretion accounted for approximately 20% of the administered dose (ABRAXIS Oncology, A division of American Pharmaceutical Partners, Inc., Schaumburg, IL 60173, USA; 2005), thus supporting a role for hepatic handling and biliary excretion of albumin nanoparticles (or its components).

Nanoparticles assembled from synthetic polymers have also received much attention in cancer drug delivery.28 One interesting example is doxorubicin-loaded poly(alkyl cyanoacrylate) (PACA) nanoparticles. In vitro studies have indicated that PACA nanoparticles can overcome drug resistance in tumor cells expressing multidrug-resistance-1-type efflux pumps.29 The mechanism of action is related to adherence of PACA nanoparticles to tumor cell plasma membrane, which initiates particle degradation and provides a concentration gradient for doxorubicin, and diffusion of doxorubicin across the plasma membrane following formation of an ion pair between the positively charged doxorubicin and the negatively charged cyanoacrylic acid (a nanoparticle degradation product).29 These observations clearly indicate that drug release and nanoparticle degradation must occur simultaneously, yielding an appropriate size complex with correct physi-cochemical properties for diffusion across the plasma membrane. Further developments with PACA nanoparticles include preparations that contain doxorubicin within the particle core and cyclosphorin, an inhibitor of the P-glycoprotein, at the surface.30 Similar to liposomes, long-circulating versions of PACA nanoparticles have also been engineered for passive as well as active targeting to solid tumors.31

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