Paclitaxel in tyrosine-derived nanospheres as a potential anti-cancer agent: In vivo evaluation of toxicity and efficacy in comparison with paclitaxel in Cremophor

Abstract

Paclitaxel (PTX) has gained widespread clinical use yet its administration is associated with significant toxicity. In the present study, the toxicity and anti-tumor efficacy of tyrosine-derived nanospheres (NSP) for the delivery of PTX was compared to a clinical formulation of PTX in PBS-diluted Cremophor® EL (PTX–CrEL-D). Maximum tolerated dose was determined using a concentration series of PTX in NSP and CrEL-D, with toxicity assessed by measuring changes in body weight. Healthy mice administered PTX–NSP continued to gain weight normally while treatment with PTX–CrEL-D resulted in significant weight loss that failed to recover following treatment. Even at the dose of 50 mg/kg, PTX–NSP showed better tolerance than 25 mg/kg of PTX–CrEL-D. Xenograft studies of breast cancer revealed that the anti-tumor efficacy of PTX–NSP was equal to that of PTX–CrEL-D in tumors originating from both MDA-MB-435 and ZR-75-1 cancer lines. Larger volume of distribution and longer half-life were measured for PTX–NSP administration compared to those reported in the literature for a CrEL formulation. This trend suggests the potential for improved therapeutic index of PTX when administered via NSP. The findings reported here confirm that the NSP formulation is an efficient method for PTX administration with significant increase in maximum tolerated dose, offering possible clinical implications in the treatment of breast tumors.

Synergistic anti-cancer mechanisms of curcumin and paclitaxel for growth inhibition of human brain tumor stem cells and LN18 and U138MG cells

“…It is noteworthy that we have achieved significant anti-cancer efficacy with low dose of PTX (10 nM) in our current in vitro combination therapy, whereas we have used 10 times more PTX (100 nM) to achieve significant anti-cancer efficacy in a previous combination therapy in animals (George et al, 2009). Use of high dose of PTX in cancer therapy in animals has been associated with severe side effects (Sheihet et al, 2012) and high mortality rates (Vassileva et al, 2007). Adverse events are also most frequently observed in cancer patients after treatment with high dose of PTX (van Herpen et al, 2010).…”

Nanoparticles and nanofibers for topical drug delivery

“…These nanospheres form strong complexes with hydrophobic molecules, as demonstrated using the model compound DAF, and clinically used antitumor agent paclitaxel, a powerful chemotherapeutic drug [28]. In contrast, TyroSpheres do not strongly associate with hydrophilic compounds such as fluorescein [29,30]. Batheja et al demonstrated that a gel formulation of TyroSpheres loaded with Nile red (a hydrophobic model drug) significantly enhanced skin permeation (1.4–1.8 fold) compared to an aqueous dispersion of Nile red-loaded TyroSpheres, both in vitro and in vivo [31].…”

“…Batheja et al demonstrated that a gel formulation of TyroSpheres loaded with Nile red (a hydrophobic model drug) significantly enhanced skin permeation (1.4–1.8 fold) compared to an aqueous dispersion of Nile red-loaded TyroSpheres, both in vitro and in vivo [31]. As these TyroSpheres are suitable only for hydrophobic drugs, they have been extensively studied for the binding and delivery of various therapeutic agents that are hydrophobic and water-insoluble, for example curcumin (unpublished data), cyclosporine A [32], sildenafil [33], rolipram [34] and paclitaxel [30,35,36]. Moreover, these nanospheres are stable for about 6 months, after which time they degrade, most likely through hydrolysis of their ester bonds [28].…”

“…Paclitaxel-loaded TyroSpheres have been shown to effectively deliver paclitaxel to tumor cells as determined using an in vitro cell killing assay [37]. In addition, in vivo studies were performed to compare the toxicity and anti-tumor efficacy of paclitaxel administered intravenously using TyroSpheres or commercially available Cremophor® EL in two breast cancer murine xenograft models [30]. It was shown that animals treated with paclitaxel-loaded Cremophor® EL lost significant weight and failed to recover following treatment, whereas those treated with paclitaxel-loaded TyroSpheres gained weight normally.…”

Advanced drug delivery nanosystems (aDDnSs): a mini-review

“…According to the recent literature, nanospheres have been already introduced as a versatile platform that can be adopted for anticancer drugs and target specific applications and have the potential to be combined with the clinically emerging method of targeted therapy (Sheihet et al, 2012;Bushman et al, 2013). Open-ended, multi-wall carbon nanotubes (CNTs) with magnetic nanoparticles encapsulated within their graphitic walls were fabricated for biomedical and pharmaceutical applications (Pagona & Tagmatarchis, 2006;Spitalsky et al, 2009;Vermisoglou et al, 2011) (Figure 1).…”