Article

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

Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, People's Republic of China.
Biomacromolecules (Impact Factor: 5.79). 06/2012; 13(8):2429-38. DOI: 10.1021/bm3006819
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
196 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The combination of chemotherapeutic drugs with different pharmacological action has emerged as a promising therapeutic strategy in the treatment of cancers. Present study examines the antitumor potential of paclitaxel (PTX) and etoposide (ETP)-loaded PLGA nanoparticles for the treatment of osteosarcoma. The resulting drug-loaded PLGA NP exhibited a nanosize dimension with uniform spherical morphology. The NP exhibited a sustained release profile for both PTX and ETP throughout the study period without any sign of initial burst release. The combinational drug-loaded PLGA NP enhanced the cytotoxic effect in MG63 and Saos-2 osteosarcoma cell lines, in comparison to either native drug alone or in cocktail combinations. Additionally, NPs showed an appreciable uptake in MG63 cells in a time-based manner. Co-delivery of anticancer drugs resulted in enhanced cell cycle arrest and cell apoptosis. The results clearly showed that combinational drugs remarkably improved the therapeutic index of chemotherapeutic drugs. The greater inhibitory effect of nanoparticle combination would be of great advantage during systemic cancer therapy. Taken together, our study demonstrated that PTX-ETP/PLGA NP based combination therapy holds significant potential towards the treatment of osteosarcoma.
    Journal of Nanobiotechnology 01/2015; 13(1):22. DOI:10.1186/s12951-015-0086-4 · 4.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study, a novel nanoparticulate drug delivery platform with inherent targeting ability to hepatic carcinoma cells and reduction-triggered drug release property was developed based on reducible cholesterol-modified pullulan (rCHP). The nanoparticle characteristics and antitumor effects were investigated in vitro and in vivo. The results revealed that drug-loaded rCHP nanoparticles were spherical and their diameter ranged between 80 and 160 nm with a change of molecular structure and drug loading content. rCHP nanoparticles with pullulan shells could anchor to human hepatocellular carcinoma cells (HepG2) due to specific recognition of asialoglycoprotein receptors (ASGPRs) overexpressing at the cytomembrane, reduction-sensitively release doxorubicin (DOX) in tumor cells, and effectively suppress the growth of HepG2 in vitro. In a hepatoma-bearing nude mouse model, attributed to their uncharged pullulan surface layer, the nanoparticles efficiently accumulated in the tumor site and were internalized by tumor cells. After cellular uptake, DOX release triggered by the reductive circumstance of tumor cells was achieved benefiting from the reduction-sensitive DOX release property. These nanoparticles showed significantly better antitumor effect and biosafety than DOX·HCl in the nude mice bearing hepatocellular carcinoma tumor.
    06/2014; 2(22):3500. DOI:10.1039/c4tb00321g
  • [Show abstract] [Hide abstract]
    ABSTRACT: Reversibly shell cross-linked micelles based on a lipoic acid (LA) decorated triblock copolymer poly(ethylene glycol)-b-poly(γ-benzyl-L-glutamate)-b-poly(L-phenylalanine) (PEG-PGlu(EDA-LA)-PPhe) have been developed for active loading and efficient intracellular delivery of DOX. The triblock copolymer was synthesized through consecutive ring-opening polymerization of cyclic monomers γ -benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) and L-phenylalanine N-carboxyanhydride (Phe-NCA) using amino-terminated poly(ethylene glycol) (PEG-NH2) as macroinitiator, followed by conjugation with LA for reversible cross-linking. The amphiphilic polymer was self-assembled to core shell corona micelles, which could be further crosslinked in the presence of a catalytic amount of dithiothreitol (DTT) in phosphate buffer (pH 7.4) to form shell-cross-linking micelles (SCLM). The SCLM showed excellent stability under physiological conditions but rapid dissociation and drug release in reductive environments mimicking those of the cytoplasm and the cell nucleus. Confocal laser scanning microscopy further demonstrated that DOX was delivered and released into the nuclei of HeLa cells following 12 h incubation with DOX-loaded SCLM. MTT assays revealed that DOX-loaded SCLM had similar anti-tumor activity as non-cross-linked micelles (NCLM) for HeLa cells following 48 h incubation. PEG-PGlu(EDA-LA)-PPhe micelles displayed low cytotoxicity up to a concentration of 1.0 mg/mL. These biodegradable reversibly shell-cross-linked micelles provide a promising platform for intelligent intracellular drug delivery in clinical chemotherapy.
    RSC Advances 02/2015; DOI:10.1039/C4RA12255K · 3.71 Impact Factor