Reduction-Responsive Disassemblable Core-Cross-Linked Micelles Based on Poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide)-Lipoic Acid Conjugates for Triggered Intracellular Anticancer Drug Release
Reduction-sensitive reversibly core-cross-linked micelles were developed based on poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide)-lipoic acid (PEG-b-PHPMA-LA) conjugates and investigated for triggered doxorubicin (DOX) release. Water-soluble PEG-b-PHPMA block copolymers were obtained with M(n,PEG) of 5.0 kg/mol and M(n,HPMA) varying from 1.7 and 4.1 to 7.0 kg/mol by reversible addition-fragmentation chain transfer (RAFT) polymerization. The esterification of the hydroxyl groups in the PEG-b-PHPMA copolymers with lipoic acid (LA) gave amphiphilic PEG-b-PHPMA-LA conjugates with degrees of substitution (DS) of 71-86%, which formed monodispersed micelles with average sizes ranging from 85.3 to 142.5 nm, depending on PHPMA molecular weights, in phosphate buffer (PB, 10 mM, pH 7.4). These micelles were readily cross-linked with a catalytic amount of dithiothreitol (DTT). Notably, PEG-b-PHPMA(7.0k)-LA micelles displayed superior DOX loading content (21.3 wt %) and loading efficiency (90%). The in vitro release studies showed that only about 23.0% of DOX was released in 12 h from cross-linked micelles at 37 °C at a low micelle concentration of 40 μg/mL, whereas about 87.0% of DOX was released in the presence of 10 mM DTT under otherwise the same conditions. MTT assays showed that DOX-loaded core-cross-linked PEG-b-PHPMA-LA micelles exhibited high antitumor activity in HeLa and HepG2 cells with low IC(50) (half inhibitory concentration) of 6.7 and 12.8 μg DOX equiv/mL, respectively, following 48 h incubation, while blank micelles were practically nontoxic up to a tested concentration of 1.0 mg/mL. Confocal laser scanning microscope (CLSM) studies showed that DOX-loaded core-cross-linked micelles released DOX into the cell nuclei of HeLa cells in 12 h. These reduction-sensitive disassemblable core-cross-linked micelles with excellent biocompatibility, superior drug loading, high extracellular stability, and triggered intracellular drug release are promising for tumor-targeted anticancer drug delivery.
"Li et al. found that the size of hydrophilic nanogel sharply decreased by adding DTT, whereas the cleavage of the disulfide linkage caused a large increase of the particle size in the case of nanogels composed of amphiphilic copolymer segments . Zhong et al. demonstrated that the cross-linked micelles increased significantly in size after being treated with DTT, followed by the dissociation into unimers upon dilution to a concentration lower than their CMC . The precursor of our nanogel Fig. 3. Degradation of nanogels over time as determined by (a) DLS, (b) UV–Vis, and (c) TEM. "
[Show abstract][Hide abstract] ABSTRACT: A novel pH and redox dual-responsive prodrug nanogel was prepared by an inverse nanoprecipitation method, which is mild and surfactant free, and based on a thiol-disulfide exchange reaction and thiol-Michael addition reaction. Highly biocompatible hyperbranched polyglycerol (hPG) was cross-linked with disulfide bonds, to obtain biodegradable nanogels, which could be degraded under intracellular reductive conditions. Doxorubicin (DOX) was conjugated to the biodegradable nanogel matrix via an acid-labile hydrazone linker. This is the first dual-responsive prodrug nanogel system that shows very low unspecific drug leaching, but efficient intracellular release of the payload triggered by the intracellular conditions. Two different prodrug nanogels were prepared with a size of approximately 150 nm, which is big enough to take the advantage of the enhanced permeation and retention (EPR) effect in tumor tissue. Cell culture analysis by microscopy and flow cytometry revealed that the prodrug nanogels were efficiently internalized by tumor cells. Distinct release profiles of DOX were achieved by adjusting the nanogel architecture, and online detection of cytotoxicity showed that, unlike free DOX, the dual-responsive prodrug nanogels exhibited a delay in the onset of toxicity, indicating the different uptake mechanism and the need for prodrug activation to induce cell death.
"Nanosized drug carriers using natural or artificial polymers appear to be a promising and reliable approach to cancer treatment, with enhanced antitumor efficacy and reduced toxic side effects . Compared with conventional systemic chemotherapies, nanosized anticancer carriers have favorable properties based on well-preprogrammed structures, such as high drug-loading capacity, high stability by avoiding rapid clearance by the renal and reticuloendothelial systems (RES) and minimized drug loss during blood circulation , enhanced accumulation in tumors through the enhanced permeability and retention (EPR) effect  and facilitated drug release triggered by environmental stimuli in the tumor sites (e.g., temperature   , pH    and glutathione  ). Several nanomedicines have been approved for clinical use, such as Doxil and Abraxane, which have been used as effective treatments for metastatic breast cancer and recurrent ovarian cancer  . "
[Show abstract][Hide abstract] ABSTRACT: An amphiphilic anionic copolymer, methoxy poly(ethylene glycol)-b-poly(L-glutamic acid-co-L-phenylalanine) (mPEG-b-P(Glu-co-Phe)), with three functionalized domains, was synthesized and utilized as a nanovehicle for cationic anticancer drug doxorubicin hydrochloride (DOX·HCl) delivery via electrostatic interactions for cancer treatment. The three domains displayed distinct functions: PEG block chain for prolonged circulation, the poly(phenylalanine) domain for stabilizing the nanoparticle construct through hydrophobic/aromatic interactions, and the poly(glutamic acid) domain for providing electrostatic interactions with the cationic drug to be loaded. The copolymer could self-assemble into micellar-type nanoparticles and DOX was successfully loaded into the interior of nanoparticles by simple mixing of DOX·HCl and the copolymer in the aqueous phase. DOX-loaded mPEG-b-P(Glu-co-Phe) nanoparticles (DOX-NPs) had a superior drug loading content (21.7%) and a high loading efficiency (almost 98%) and a pH-triggered release of DOX. The size of DOX-NPs was approximately 140 nm as determined by dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM). In vitro assays showed that DOX-NPs exhibited the higher cell proliferation inhibition and the higher cell uptake in A549 cell lines compared with free DOX·HCl. Maximum tolerated dose (MTD) studies showed the DOX-NPs demonstrated an excellent safety profile with a significantly higher MTD (15 mg DOX/kg) than that for free DOX·HCl (5 mg DOX/kg). The in vivo studies on the subcutaneous non-small cell lung cancer (A549) xenograft nude mice model confirmed DOX-NPs had significant antitumor activity and reduced side effects, and then enhanced tumor accumulation due to the prolonged circulation in blood and the enhanced permeation and retention (EPR) effect compared with free DOX, indicating its great potential for cancer therapy.
"Lipoic acid (LA) shows antioxidant activity in both, water and fatty tissues, giving it an unusually broad spectrum of antioxidant action.    By virtue of its numerous advantageous properties, including good water-and fat-solubility as well as moisturizing, anti-inflammatory, photoprotective, and antioxidant properties, LA is commonly used in cosmetics to produce a wide range of facial and body care products as well as skin protection formulas with anti-wrinkle effects.  The development of new cosmetic delivery systems has been most heavily influenced by two factors: the development of new synthetic surfactants, and the understanding of the structure of the skin and its function in relation to percutaneous absorption, both of which occurred about 50 years ago. "
[Show abstract][Hide abstract] ABSTRACT: Rationale:
Currently, most of the antioxidants and free radical neutralizers used in cosmetic compositions are absorbed quickly into deeper layers of skin, and then carried away by the blood stream. It would be beneficial to delay the penetration of antioxidants to the deeper layers of skin to control their delivery and release.
Recently, growing attention has been paid to the attachment of cosmetics to specific polymer carriers. Biodegradable and biocompatible conjugates of oligo-3-hydroxybutyrate with lipoic acid were obtained via the anionic ring-opening oligomerization of (R,S)-β-butyrolactone initiated by lipoic acid potassium salt. The structure of the resulting conjugates as well as their water-soluble hydrolytic degradation products were established at the molecular level by electrospray ionization mass spectrometry (ESI-MS(n)) supported by (1)H NMR analyses.
The structural studies, performed with the aid of ESI-MS(n), confirmed that the lipoic acid was covalently bound to oligo-3-hydroxybutyrate chains through hydrolyzable ester bonds. Furthermore, hydrolytic degradation studies of the bioconjugates provided detailed insight into the hydrolysis process, allowing the identification of the degradation products and confirming the release of α-lipoic acid. Cytotoxicity tests demonstrated that the conjugates were non-toxic.
Detailed molecular structural studies of new polymeric delivery systems of lipoic acid were performed by ESI-MS. ESI-MS proved to be an excellent technique for the evaluation of hydrolytic degradation products of the conjugates and for monitoring the release of lipoic acid. The results obtained contribute significantly to the characterization of biocompatible LA-OHB conjugates with potential applications in cosmetology.
Rapid Communications in Mass Spectrometry 04/2013; 27(7):773-783. DOI:10.1002/rcm.6509 · 2.25 Impact Factor
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