Improved antifungal activity of itraconazole-loaded PEG/PLA nanoparticles

Abstract

Poly(ethylene glycol)/polylactic acid (PEG/PLA) nanoparticles (NPs) containing the hydrophobic antifungal itraconazole (ITZ) were developed to provide a controlled release pattern of ITZ as well as to improve its aqueous dispersibility and hence enhance its antifungal action. Two PEG/PLA copolymers (PEGylated PLA polymers) were used in this study; branched PEGylated polymer in which PEG was grafted on PLA backbone at 7% (mol/mol of lactic acid monomer), PEG7%-g-PLA, and multiblock copolymer of PLA and PEG, (PLA-PEG-PLA)n with nearly similar PEG insertion ratio and similar PEG chain length. ITZ-loaded PLA NPs were also prepared and included in this study as a control. ITZ-NPs were prepared from a 1 : 1 w/w blend of PLA and each PEGylated polymer either PEG7%-g-PLA or (PLA-PEG-PLA)n using an oil-in-water emulsion evaporation method. The NPs morphology, size and size distribution, zeta potential, loading efficiency, release profile and antifungal activity were characterized. All ITZ-NPs were nearly spherical with smooth surface and showed less aggregating tendency with a size range of 185-285 nm. All ITZ-NPs measured nearly neutral zeta potential values close to 0 mV. The % LE of ITZ was ∼94% for PEG7%-g-PLA NPs and ∼83% for (PLA-PEG-PLA)n at 15.3% w/w theoretical loading. PEG/PLA NPs were stable over time regarding size and size distribution and % ITZ loading efficiency (% LE). ITZ release showed an initial burst followed by a gradual release profile for ITZ-NPs over 5 days. (PLA-PEG-PLA)n NPs exhibited faster release rates than PEG7%-g-PLA NPs particularly at the last 2 days. Differential scanning calorimetry and powder X-ray diffractometry data confirmed that ITZ exists in an amorphous state or a solid solution state into the NPs matrix. Fourier transform infrared revealed the possibility of chemical interaction between ITZ and the NPs matrix polymer indicating the successful entrapment of ITZ inside the particles. In haemolysis test, ITZ-NPs caused mild haemolysis over the concentration range (5-20 µg/mL) compared to free ITZ, indicating better safety profile of ITZ-NPs. ITZ-loaded PEG/PLA NPs inhibited fungal growth more efficiently than either free ITZ or ITZ-loaded PLA NPs. Our results suggest that PEG/PLA-ITZ could be used efficiently as a nanocarrier to improve the aqueous dispersibility of ITZ, control its release over time and, thereby, enhance its antifungal efficacy.

Synthesis and Evaluation of Symmetrically PEG‐Decorated Triglycerides of Fatty Acid as Drug‐Encapsulating Agents

“…The encapsulation test results obtained in the present study (Table ) showed that the increase in length of PEG chains does not lead to a higher drug loading. In general, the observed ITZ content, reaching the maximum value of 6.48% w/w in the case of the product 11 , are comparable with some recently proposed ITZ encapsulation systems based on poly(ethylene glycol)/poly(lactic acid) (PEG/PLA) nanoparticles and micelles formed by PEGylated bile acids and, therefore, could be considered as being satisfactory for a potentially drug delivery material.…”

Influence of Hydrophobic Dendrimer Core Structure on the Itraconazole Encapsulation Efficiency

“…The results of the in vitro tests performed with the synthesized dendrimers 6 , 25 , 29 , and 30 are shown in Figure A. In general, the drug content observed in the case of the structures 6 , 30 , and 25 is comparable with other recently proposed ITZ encapsulation systems based on PLA‐PEG nanoparticles and PEGylated bile acid micelles . Based on the obtained data, preliminary conclusions about key structural factors responsible for the observed effects could be drawn by comparing such parameters of dendrimers as molecular mass, size, and nature of hydrophilic and hydrophobic segments.…”

“…Nevertheless, the bioavailability of unformulated crystalline ITZ is extremely low, in particular, due to its very low solubility in water, about 1 ng mL −1 in aqueous solutions at pH from 1 to 13 . To overcome this problem, various drug formulations have been recently developed such as solid solutions in poly(ethylene glycol), mixtures with water‐soluble laponite clay, and phosphoric acid, solid dispersions and hot‐stage extrusions with water‐soluble hydroxypropylmethylcellulose (HPMC), liposomes, as well as solid nanoparticles based on polylactic acid‐poly(ethylene glycol) (PLA‐PEG) polymers, micelles formed by PEGylated bile acids, etc. However, in practice, the number of excipients for encapsulation of ITZ is not so large.…”

Poly(lactic acid)–poly(ethylene glycol) nanoparticles provide sustained delivery of a Chlamydia trachomatis recombinant MOMP peptide and potentiate systemic adaptive immune responses in mice

“…Encapsulation within PLA-PEG has tremendous benefits in vivo including protecting the integrity and activity of biomolecules while augmenting their immune-potentiating effects. This copolymer apparently enhances the therapeutic activity of encapsulated drugs 5,7 and consequently is more commonly used for drug delivery. Conversely, it is not widely exploited for vaccine delivery 8 , in spite of its aforementioned inherent properties, which are desirable for vaccines.…”