PHResponsive Systems

The pH where drug release is triggered can be adjusted by varying the pH-sensitive moiety incorporated in the copolymer.158,187 In this way, the pH phase transition of a micelle system can be designed to suit targets that have different pH values. For instance, micelles that are stable at pH ~ 2 and are disrupted at pH > 7.2 may be suitable for oral delivery of hydrophobic drugs. As an example, a 10-fold increase in the bioavailability of fenofibrate formulated in pH-re-sponsive micelles was reported.188 In the case of tumor targeting, micelles with a phase transition of approximately pH 7.0 could be beneficial as tumor tissues are known to be slightly more acidic

187 189 190

(mean pH 7.0) than normal tissues (pH 7.4). , 9,9 If subcellular targeting is desired, cytoplasmic accumulation of drugs can be enhanced by utilizing micelles that are responsive to pH values

187 191 192

ranging from 5.0 to 6.0 (endosomal/lysosomal pH). , , pH-responsive micelles have also been developed by conjugating drugs to the hydrophobic blocks of copolymers using pH-sensitive linkages. For instance, doxorubicin can be conjugated to PEG-b-P(Asp) copolymers via a hydrazone linkage. The micelles formed from this copolymer were found to be extracellularly stable, and they provided selective release of doxorubicin in the endo-somes where the pH ranges from 5.0 to 6.0. The released drug was found to first localize in the cytoplasm and eventually in the nucleus. The pH-responsive doxorubicin micelles were also shown to be capable of infiltrating avascular multicellular tumor spheroids in a uniform manner. Furthermore, the micelles were effective in suppressing tumor growth in a murine C26 colon tumor model and increased the MTD by more than 2.5 times because of their secure drug encapsulation.191,192 Another approach to develop pH-responsive micelles is to disrupt micelle formation in the acidic environment by introducing titrable groups into the copolymer.187 Leroux's group introduced a hydrophilic titrable monomer (methacrylic acid or MAA) into the poly(N-isopropylacrylamide)-co-octadecyl acrylate (poly(NIPA)-co-ODA) copolymer to form pH-respon-sive micelles for PDT.158 These micelles were found to undergo a pH phase transition and structural changes in the micelle core at a pH of approximately 5.8. The enhanced cytotoxicity of the AICIPc-loaded poly(NIPA)-co-ODA-co-MAA micelles were found to be highly dependent on the pH-gradient between the cytoplasm and the endosomal/lysosomal compartments.158

Bae and co-workers have developed several pH-responsive micelle systems by using poly (L-histidine) (polyHis) as the pH-sensitive moiety. The CMC of the PEG-b-polyHis copolymer was found to increase as the pH of the media was decreased with an abrupt increase in the CMC occurring at a pH of 7.2. Therefore, with the appropriate alteration in pH, these micelles become thermodynamically unstable and dissociate, resulting in the release of their contents.193 Doxoru-bicin-loaded PEG-b-polyHis micelles were shown to result in a significant increase in the in vitro intracellular accumulation of drug, in vivo tumor localization of drug, and tumor growth inhibition in the A2780 ovarian tumor model via extracellular pH-dependent targeting of the tumor.194 The addition of polyHis to PEG-b-PDLLA further reduces the pH phase transition of the micelles to the range of 6.6-7.2. These micelles were further modified with ligand coupling to achieve a doubletargeting effect.181,190 For example, Lee et al. prepared polyHis-b-PEG-b-PDLLA mixed micelles with biotin as the targeting ligand. Biotin is protected by the PEG shell at pH > 7.0 and is exposed on the surface of micelles when the pH is decreased to 6.5-7.0 (extracellular tumor pH). As the pH is further reduced to less than 6.5 (endosomal pH), the micelles destabilize, triggering drug release and disrupting endosomal membranes via the proton-sponge effect.190 In the future, it is anticipated that combinations of sensing mechanisms will be used to improve the effectiveness of micellar-drug targeting to the site of interest.

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