Huihui Kuang

Biodegradable amphiphilic copolymer containing nucleobase: synthesis, self-assembly in aqueous solutions, and potential use in controlled drug delivery.

Biodegradable nucleobase-grafted amphiphilic copolymer, the methoxyl poly (ethylene glycol)-b-poly (L-lactide-co-2-methyl-2(3-(2,3-dihydroxylpropylthio) propyloxycarbonyl)-propylene carbonate/1-carboxymethylthymine) (mPEG-b- P(LA-co-MPT)), was synthesized. (1)H NMR titration and FT-IR spectroscopy indicated that the hydrogen-bonding could be formed between mPEG-b-P(LA-co-MPT) and 9-hexadecyladenine (A-C16). The hydrophobic microenvironment of the amphiphilic copolymer can protect the complementary multiple hydrogen bonds between mPEG-b-P(LA-co-MPT) and A-C16 from water effectively. The addition of A-C16 not only lowered the critical aggregation concentration (CAC) of mPEG-b-P(LA-co-MPT)/A-C16 nanoparticles (NPs) in aqueous solution but also induced different morphologies, which can be observed by transmission electron microscopy (TEM). Meanwhile, dynamic light scattering (DLS) and turbidometry was utilized to evaluate the effect of temperature and pH change on the stability of mPEG-b-P(LA-co-MPT)/A-C16 NPs. Cytotoxicity evaluation showed good biocompatibility of the mPEG-b-P(LA-co-MPT)/A-C16 NPs. The in vitro drug release profile showed that with the increase of A-C16 content, the doxorubiucin (DOX) release at pH 7.4 decreased, while the faster release rate was observed with the addition of A-C16 with a pH of 5.0. Importantly, DOX-loaded NPs exerted comparable cytotoxicity against MDA-MB-231 cells. This work provided a new method to stabilize NP structure using hydrogen-bonds and would have the potential to be applied in controlled drug delivery.

Synthesis of mesoporous silica nanoparticle–oxaliplatin conjugates for improved anticancer drug delivery

Mesoporous silica nanoparticles (MSN) with 1,2-bidentate carboxyl groups on the surface reacted with 1,2-diaminecyclohexano platinum(II) dinitrate (DACH-Pt-(NO3)2) which is an active anticancer species of clinic relevant oxaliplatin to form MSN-Pt. The modification of the parent particles was monitored by (13)C, (29)Si solid-state NMR, X-ray measurements (XRD) and Fourier transform infrared spectroscopy (FT-IR). After loading with platinum drugs, MSN-Pt exhibited two strong Pt4f signals as indicated by X-ray photoelectron spectroscopy (XPS). The platinum content in the conjugates was calculated to be 9.7% according to ICP-MS measurements. Confocal laser scanning microscopy (CLSM) displayed that MSN-Pt were uptaken fast by HepG-2 cells and concentrated within endosomes and lysosomes. In vitro MTT assay of MSN-Pt demonstrated an improved cytotoxicity against HepG-2 cells than that of free oxaliplatin. This is due to the fact that MSN-Pt expressed higher platinum intracellular uptake and more DNA binding (Pt-DNA adducts) than free oxaliplatin. Hence this work highlighted that the platinum loaded MSN nanoparticles could be a promising future intelligent drug delivery system.

Core-crosslinked amphiphilic biodegradable copolymer based on the complementary multiple hydrogen bonds of nucleobases: synthesis, self-assembly and in vitro drug delivery

Nucleobases (adenine and thymine) were conjugated to the amphiphilic biodegradable copolymers methoxyl poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2-allyloxycarbonylpropylene carbonate) (mPEG-b-P(LA-co-MAC)). The hydrogen bonds between adenine (A) and thymine (T) were confirmed by 1H NMR titration experiments and FT-IR. It was found that the incorporation of nucleobases into the hydrophobic segment of the amphiphilic copolymers could be used for core-crosslinking of the formed micelles containing a lowered critical micelle concentration (CMC) via hydrogen bond interaction between A and T in aqueous solution. The anticancer drug doxorubicin (DOX) was encapsulated into the copolymer micelles. The in vitro drug release profile showed that the incorporation of nucleobases significantly restricted DOX release at pH 7.4, because of the compact crosslinking structure of micelles. However, a much faster release rate was observed at pH 5.0, due to the dissociation of hydrogen bonds between nucleobases. This character facilitates drug delivery in the acidic tumor micro-environment inside the endosome. Meanwhile, the DOX-loaded core-cross-linked micelles could be efficiently internalized into cancer cells and exhibit similar anticancer efficacy as free DOX against MDA-MB-231 cells. Therefore, the complementary multiple hydrogen bonds of nucleobases provided a convenient tool to stabilize the micelle structures by forming core-crosslinking, and could be further applied for controlled drug delivery.

A reduction-sensitive carrier system using mesoporous silica nanospheres with biodegradable polyester as caps

Mesoporous silica nanoparticles (MSN)-polymer hybrid combined with the aliphatic biodegradable polyester caps on the surface were first developed in order to manipulate the smart intracellular release of anticancer drugs. First, poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) was successfully grafted on the surface of MSN via disulfide bonds which could cleave under a reduction environment in tumor cells. The anticancer drug doxorubicin (DOX) was encapsulated into the particle pores. The in vitro drug release profile showed that DOX release was significantly restricted by the polymer caps at pH 7.4, while it was greatly accelerated upon the addition of GSH. Cytotoxicity evaluation showed good biocompatibility with the hybrid particles. Fast endocytosis and intracellular DOX release were observed by confocal laser scanning microscopy (CLSM). The DOX-loaded particles exhibited comparable antitumor activity with free DOX towards HeLa cells and showed in a time-dependent manner. This work developed an extensive method of utilizing aliphatic biodegradable polyesters as polymer caps for MSN to control drug delivery. The paper might offer a potential option for cancer therapy.

Facile preparation of core cross-linked micelles from catechol-containing amphiphilic triblock copolymer

Efficient delivery of anti-cancer drugs into tumor cells for enhancing the intracellular drug concentration is a major challenge for cancer therapy due to the instability of drug-loading vehicle. In this report, we developed a simple method to stabilize the nanostructure of micelles only by bubbling air to crosslink the outer layer of the micelle core. Dopamine was conjugated to a biodegradable triblock copolymer monomethoxy poly(ethylene glycol)-b-poly(2-methyl-2-carboxyl-propylene carbonate)-b-poly(L-lactide) (mPEG-b-PMCC-b-PLA) to obtain dopamine grafted copolymer mPEG-b-P(MCC-g-dopamine)-b-PLA. After self-assembly, the core cross-linked micelles were then prepared by the oxidative self-polymerization of dopamine in the middle hydrophobic phase of the micelles. The cross-linked micelles had smaller sizes and narrower particle size distributions than their uncross-linked precursors. The improved stability was confirmed by critical micelle concentration (CMC) experiments and 1H NMR spectra. The kinetics and processes of oxidative cross-linking of micelles under air flux were monitored by UV-Vis spectroscopy and transmission electron microscopy (TEM). These core cross-linked micelles were able to load doxorubicin (DOX) with superior loading capacity of up to 19.5% (w/w, drug/micelle) with high drug loading efficiency (97.5%). Compared with the uncross-linked ones, drug release efficacy from the cross-linked micelles extremely decreased at pH 7.4. However, a properly sustained release occurred at pH 5.0, which is very favorable for drug delivery in tumor cells. The DOX-loaded micelles had similar cytotoxicity as the free drug and could be effectively internalized into MDA-MB-231 cells. This controllable and convenient approach for preparing core cross-linked micelles will have a pragmatic future in stabilizing the architecture of nanocarriers for drug delivery.

Acetalated-dextran as valves of mesoporous silica particles for pH responsive intracellular drug delivery

A pH-sensitive drug release system using acetalated-dextran as valves was designed to manipulate smart intracellular release of anticancer drugs. Dextran was grafted onto the exterior of MSN through a click reaction, and followed by acetalation to generate the final carriers of MSN–Dex-Ac. The hydrophobic Dex-Ac would act as valves on the MSN surface to block the entrapped drugs inside the MSN pores. While under acidic conditions mimicking the micro-environment of endosomal/lysosomal compartments, the valves could be opened by acetal hydrolysis to recover the acetalated-dextran to its hydrophilic state, resulting in fast drug release. In vitro drug release profile clearly showed that DOX release was restricted at pH 7.4 by the valves, while it was accelerated under acidic conditions. Fast endocytosis and intracellular DOX release was observed by confocal laser scanning microscopy (CLSM). Cytotoxicity evaluation showed good biocompatibility with the carriers. In vitro MTT assays revealed that the DOX-loaded particles exhibited comparable antitumor activity with free DOX towards HeLa cells.

Double pH-responsive supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases and acetalated dextran for drug delivery†

A double pH-responsive supramolecular copolymer micelle was successfully developed, which was based on complementary multiple hydrogen bonds of nucleobases and acetalated dextran. The thymine-terminated poly(ethylene glycol) (T-PEG-T) and adenine-terminated acetalated dextran (AcDEX-A) were synthesized and used to construct supramolecular amphiphilic triblock copolymer AcDEX-A:T-PEG-T:A-AcDEX, which could be further self-assembled into supramolecular micelles in water. These micelles were stable at pH 7.4, but disruptive at pH 5.0 due to the double pH-sensitivity of hydrogen bonds within the copolymer backbones and the hydrolysis of the acetalated dextran. The hydroxyl coverage of Ac-DEX had an important effect on the critical micelle concentration (CMC) and particle size of AcDEX-A:T-PEG-T:A-AcDEX micelles, which were observed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). In addition, turbidometry was utilized to evaluate the effect of pH-responsivity of AcDEX-A:T-PEG-T:A-AcDEX micelles and these supramolecular micelles were completely decomposed at pH 5.0. Cytotoxicity evaluation showed good biocompatibility of these micelles, and doxorubicin (DOX) was encapsulated into supramolecular micelles as a model drug. The in vitro drug release profile showed that the DOX release speed at pH 5.0 could be adjusted by changing the hydroxyl coverage of Ac-DEX. Meanwhile, DOX-loaded supramolecular micelles could be efficiently internalized into cancer cells and showed similar inhibition of proliferation of the Hela cell as free DOX. This work provided a new method for enabling a rapid intracellular release of drugs by using double pH-sensitive hydrogen bonds and acetalated dextran, which would have the potential to be applied in controlled drug delivery.

Novel hydroxyl-containing reduction-responsive pseudo-poly(aminoacid) via click polymerization as an efficient drug carrier

A novel biodegradable pseudo-poly(aminoacid) copolymer (mPEG–HRSCP–mPEG) was produced via a mechanism of step polymerization through Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) (click polymerization) using dialkyned-cystine and diazide monomers. The disulfide and hydroxyl groups were repeatedly arranged in the polymer backbone. The introduced hydroxyl groups could not only adjust the hydrophilicity of the amphiphilic polymer, but also improve the DOX loading efficiency and solubility. Compared with the unmodified one, the polymer containing hydroxyl groups has increased hydrophilicity with a larger critical aggregation concentration (CAC) value, lower water contact angle, higher drug loading content and drug loading efficiency. The pH and reduction sensitivities of this drug delivery system (DDS) were investigated using Dynamic Light Scattering (DLS) to monitor the changes of average diameters. DOX was loaded as a model drug and in vitro release experiments demonstrated that DOX release was accelerated by an addition of 10 mM glutathione (GSH) or under acidic conditions rather than under physiological conditions. Our study on in vitro anticancer efficiency showed that DOX-loaded nanoparticles had a higher cytotoxicity towards GSH pretreated HeLa cells. These newly designed copolymer nanoparticles can be used as novel and impactful pH and reduction dual-responsive nanocarriers for intelligent DOX delivery.

The design of peptide-amphiphiles as functional ligands for liposomal anticancer drug and gene delivery.

Abstract Liposomal nanomedicine has led to clinically useful cancer therapeutics like Doxil and DaunoXome. In addition, peptide‐functionalized liposomes represent an effective drug and gene delivery vehicle with increased cancer cell specificity, enhanced tumor‐penetrating ability and high tumor growth inhibition. The goal of this article is to review the recently published literature of the peptide‐amphiphiles that were used to functionalize liposomes, to highlight successful designs that improved drug and gene delivery to cancer cells in vitro, and cancer tumors in vivo, and to discuss the current challenges of designing these peptide‐decorated liposomes for effective cancer treatment. Graphical abstract Figure. No Caption available.

Thymine modified amphiphilic biodegradable copolymers for photo-cross-linked micelles as stable drug carriers.

A photo-cross-linked micelle is synthesized via photodimerization of thymine moieties fabricated from amphiphilic block copolymers (mPEG-b-P(LA-co-MPT). The crosslinking behavior is monitored by UV-Vis spectra and (1) H NMR. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) showed that cross-linked micelles had smaller sizes than their uncross-linked precursors. In vitro studies reveal that cross-linking of the micelle cores results in a slow drug release and faster cellular uptake in comparison with uncross-linked ones in MCF-7 and Hela cells. Moreover, the paclitaxel (PTX)-loaded core-cross-linked micelles exhibit similar anticancer efficacy as free PTX. This work provides a convenient tool for designing a more stable structure in the blood circulation to realize a controlled drug delivery.