Versatile theranostics agents designed by coating ferrite nanoparticles with biocompatible polymers.

Three biocompatible polymers, polyethylene glycol (PEG), dextran and chitosan, have been used in this work to control the colloidal stability of magnetic nanoparticles (14 ± 5 nm in diameter) and to vary the aggregation state in order to study their effect on relaxometric and heating properties. Two different coating strategies have been deeply developed; one based on the formation of an amide bond between citric acid coated nanoparticles (NPs) and amine groups present on the polymer surface and the other based on the NP encapsulation. Relaxometric properties revealed that proton relaxation rates strongly depend on the coating layer hydrophilicity and the aggregation state of the particles due to the presence of magnetic interactions. Thus, while PEG coating reduces particle aggregation by increasing inter-particle spacing leading to reduction of both T1 and T2 relaxation, dextran and chitosan lead to an increase mainly in T2 values due to the aggregation of particles in bigger clusters where they are in close contact. Dextran and chitosan coated NPs have also shown a remarkable heating effect during the application of an alternating magnetic field. They have proved to be potential candidates as theranostic agents for cancer diagnosis and treatment. Finally, cytotoxicity of PEG conjugated NPs, which seem to be ideal for intravenous administration because of their small hydrodynamic size, was investigated resulting in high cell viability even at 0.2 mg Fe ml(-1) after 24 h of incubation. This suspension can be used as drug/biomolecule carrier for in vivo applications.

Synthesis and characterization of biodegradable and thermosensitive polymeric micelles with covalently bound doxorubicin-glucuronide prodrug via click chemistry.

Doxorubicin is an anthracycline anticancer agent that is commonly used in the treatment of a variety of cancers, but its application is associated with severe side effects. Biodegradable and thermosensitive polymeric micelles based on poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAmLac(n))) have been studied as drug delivery systems for therapeutic and imaging agents and have shown promising in vitro and in vivo results. The purpose of this study was to investigate the covalent coupling of a doxorubicin-glucuronide prodrug (DOX-propGA3) to the core of mPEG-b-p(HPMAmLac(2)) micelles. This prodrug is specifically activated by human ß-glucuronidase, an enzyme that is overexpressed in necrotic tumor areas. To this end, an azide modified block copolymer (mPEG(5000)-b-p(HPMAmLac(2)-r-AzEMA)) was synthesized and characterized, and DOX-propGA3 was coupled to the polymer via click chemistry with a high (95%) coupling efficiency. Micelles formed by this DOX containing polymer were small (50 nm) and monodisperse and released 40% of the drug payload after 5 days incubation at 37 °C in the presence of ß-glucuronidase, but less than 5% in the absence of the enzyme. In vitro cytotoxicity experiments demonstrated that DOX micelles incubated with 14C cells showed the same cytotoxicity as free DOX only in the presence of ß-glucuronidase, indicating full conversion of the polymer-bound DOX into the parent drug. Overall, this novel system is very promising for enzymatically responsive anticancer therapy.

Micelles based on HPMA copolymers.

Polymeric micelles have been under extensive investigation during the past years as drug delivery systems, particularly for anticancer drugs. They are formed by the self-assembly of amphiphilic block copolymers in aqueous solutions and have a spherical shape and a size in the nano-range (<200nm). Tumor accumulation of polymeric micelles upon intravenous administration can occur as a result of the leaky vasculature of tumor tissue (called the enhanced permeation and retention (EPR) effect).To benefit from the EPR effect, polymeric micelles need to have prolonged circulation times as well as high and stable drug loadings. Poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA) is a hydrophilic polymer currently under investigation for its use in polymer-drug conjugates. Its biocompatibility, non-immunogenicity and the possibility for functionalization are properties that resulted in broad pharmaceutical and biomedical applications, also in the micelle technology research. Being hydrophilic, it can serve as a micellar stealth corona, while it can also be modified with hydrophobic moieties to serve as a micellar core in which hydrophobic drugs can be solubilized and retained. HPMA-based polymeric micelles have been showing very promising in vitro and in vivo results. This review summarizes the applications of pHPMA in the field of polymeric micelles, either serving as a micellar stealth corona, or, if hydrophobically rendered by derivatization, as a micellar core.

The influence of bile acids on the oral bioavailability of vitamin K encapsulated in polymeric micelles.

The purpose of this study was to assess the ability of polymeric micelles to enable gastrointestinal absorption of the extremely hydrophobic compound vitamin K, by comparison of its absorption in bile duct ligated and sham operated rats. Hereto, vitamin K was encapsulated in micelles composed of mPEG(5000)-b-p(HPMAm-lac(2)), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, p<0.01). Duodenal administration of polymeric micelles together with bile acids in bile duct ligated rats fully restored absorption. Dynamic light scattering time series showed a significant and dose dependent rise in micellar size in the presence of bile acids in vitro, indicating the gradual formation of mixed micelles during the first 3 h of incubation. The highest bile acid amounts (11 mM deoxycholic acid and 41 mM taurocholic acid) eventually caused aggregation of the loaded micelles after the formation of mixed micelles. These data suggest that the gastrointestinal absorption of encapsulated vitamin K from polymeric micelles is mediated by free bile and that uptake of intact micelles through pinocytosis is insignificant.