Self-Assembling PCL-Based Nanoparticles as PTX Solubility Enhancer Excipients (original) (raw)

2018, Macromolecular Bioscience

in this application has been hampered by the heterogeneity of the solid tumor microenvironments in the patients, such as different pore of the vessels, increased interstitial fluid pressure, hypoxia, and sometimes even the complete absence of vasculature. [2] A typical example of lipophilic anticancer drug loaded in NPs in an attempt to improve its therapeutic index is paclitaxel (PTX), one of the most important chemotherapeutic drugs developed so far for the treatment of a large number of cancers, such as ovarian, lung, and breast cancers. [3] PTX, isolated for the first time from the bark of the Taxus brevifolia, is a very poor water-soluble white crystalline powder that requires to be formulated with polyoxyethylated castor oil (Cremophor EL) and dehydrated ethanol (50/50 v/v) in order to be administrated. [4] However, Cremophor EL is a surfactant well-known to cause adverse effects, such as hypersensitivity reactions and peripheral neuropathy. [5] Among all the nanocarriers developed to encapsulate PTX eliminating this toxic compound, polycaprolactone (PCL) and poly(lacticco-glycolic acid) (PLGA)-based NPs have shown good profile of biocompatibility, biodegradability, and efficacy. [6] A formulation based on PLGA micelles named Genexol is, together with Abraxane, a PTX albumin-bound NP formulation, one of the currently approved PTX alternatives to the more toxic Cremophor EL-based Taxol. [7,8] The improvement in the toxicological profile, however, is probably due to different effects of the NPs, such as the removal of toxic excipients, an increased solubility, or a different rate of binding to plasma proteins. As long as the NPs play only the role of a solubility enhancer excipient, they should be able to load the drug with the highest efficiency possible and degrade into biocompatible and easy removable compounds. In the fabrication of the NPs, a significant amount of the lipophilic drug is lost during the loading and dialysis and this can cause an additional increase in the cost of a less toxic formulation. Recently, we developed a novel type of PCL-based NPs for the drug delivery of different lipophilic therapeutics including PTX and demonstrated the in vivo antitumor activity. [9] These NPs are made via a two-step process that consists in i) the synthesis of a PCL macromonomer (Figure 1, HEMA-CL 5) via ring-opening polymerization (ROP) and ii) the emulsion Drug Delivery