Xiaoqing Yi

Preparation of pH and redox dual-sensitive core crosslinked micelles for overcoming drug resistance of DOX

In this paper, we first synthesized an amphiphilic block copolymer poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-5-methyl-5-propargyl-1,3-dioxan-2-one), i.e., PEG-P(TMBPEC-co-MPMC), with pendant reactive alkynyl groups as well as pH-sensitive acetal groups. Next, core crosslinked (CCL) micelles were prepared by the introduction of 1,6-diazidohexane and bis(azidoethyl)disulfide into micelles via azide–alkyne click chemistry, which were denoted as CCL/CC and CCL/SS, respectively. The CCL micelles had superior stability and drug loading efficiency to the uncrosslinked (UCL) micelles. In comparison with free DOX, drug-loaded CCL micelles exhibited lower cell viability in MCF-7/ADR cells due to their “stealth” endocytosis effect that might be beneficial for overcoming delivery barriers of drug resistance. More interestingly, as compared with CCL/CC micelles, CCL/SS micelles were found to further enhance cytotoxicity in MCF-7/ADR cells because of their better on-demand drug release capability of pH and redox dual-sensitive CCL/SS micelles. These results suggest that the self-assembled pH and redox dual-sensitive CCL/SS micelles have promising applications to overcome multi-drug resistance in tumor treatments.

Dual-peptide-functionalized albumin-based nanoparticles with ph-dependent self-assembly behavior for drug delivery.

Drug delivery has become an important strategy for improving the chemotherapy efficiency. Here we developed a multifunctionalized nanosized albumin-based drug-delivery system with tumor-targeting, cell-penetrating, and endolysosomal pH-responsive properties. cRGD-BSA/KALA/DOX nanoparticles were fabricated by self-assembly through electrostatic interaction between cell-penetrating peptide KALA and cRGD-BSA, with cRGD as a tumor-targeting ligand. Under endosomal/lysosomal acidic conditions, the changes in the electric charges of cRGD-BSA and KALA led to the disassembly of the nanoparticles to accelerate intracellular drug release. cRGD-BSA/KALA/DOX nanoparticles showed an enhanced inhibitory effect in the growth of αvβ3-integrin-overexpressed tumor cells, indicating promising application in cancer treatments.

pH-Activated Targeting Drug Delivery System Based on the Selective Binding of Phenylboronic Acid.

Phenylboronic acid (PBA) is a tumor-targeting molecule, but its nonspecific interaction with normal cells or other components containing cis-diol residues undoubtedly limits its potential application in tumor-targeting drug delivery. Herein, we developed fructose-coated mixed micelles via PBA-terminated polyethylene glycol monostearate (PBA-PEG-C18) and Pluronic P123 (PEG20-PPG70-PEG20) to solve this problem, as the stability of borate formed by PBA and fructose was dramatically dependent on pH. The fluorescence spectroscopic results indicated that the borate formed by PBA and fructose decomposed at a decreased pH, and better binding between PBA and sialic acid (SA) was observed at a low pH. These results implied that the fructose groups decorated on the surface of the micelles could be out-competed by SA at a low pH. In vitro uptake and cytotoxicity studies demonstrated that the fructose coating on the mixed micelles improved the endocytosis and enhanced the cytotoxicity of drug-loaded mixed micelles in HepG2 cells but reduced the cytotoxicity in normal cells. These results demonstrate that a simple decorating strategy may facilitate PBA-targeted nanoparticles for tumor-specific drug delivery.

A co-delivery system based on a reduction-sensitive polymeric prodrug capable of loading hydrophilic and hydrophobic drugs for combination chemotherapy

Herein, we report a co-delivery system based on poly(ethylene glycol)-b-poly(5-methyl-5-propargyl-1,3-dioxan-2-one) (PEG-b-PMPMC) for cancer treatment. A reduction-sensitive PTX prodrug (azido-SS-PTX) was grafted onto PEG-b-PMPMC by azide–alkyne click reaction to give a reduction-sensitive polymeric prodrug, PEG-b-PMPMC-g-PTX, with a well-defined structure and narrow molecular weight distribution. Interestingly, the polymeric prodrug could self-assemble into micelles or polymersomes in aqueous solution based on the particular graft ratio of PTX on the polycarbonate backbone, which endowed it with a possibility to encapsulate a hydrophobic drug (e.g., doxorubicin, DOX) or a hydrophilic drug (e.g., doxorubicin hydrochloride, DOX·HCl) for combination chemotherapy. To promote the stability and on-demand drug release, the self-assemblies of PEG-b-PMPMC-g-PTX were further crosslinked by a reduction-sensitive crosslinker to prepare reversibly crosslinked nanoparticles. The drug release from the carriers was suppressed under normal physiological conditions, whereas markedly accelerated under 10 mM dithiothreitol (DTT) conditions. The dual drug-loaded nanoparticles exhibited significant growth-inhibition for HeLa cells and drug-resistant MCF-7/ADR cells compared with the single drug-loaded nanoparticles, especially for drug resistant tumor cells. More importantly, DOX·HCl-loaded polymersomes of the polymeric prodrug exhibited a synergistic effect of cell-growth inhibition on HeLa cells. These results indicated that the co-delivery system based on reduction-sensitive polymeric prodrugs would be a promising technology in cancer therapy to overcome multidrug resistance (MDR).

One-pot synthesis of crosslinked amphiphilic polycarbonates as stable but reduction-sensitive carriers for doxorubicin delivery.

In this paper, we first synthesized a novel disulfide-coupled bis-(cyclic carbonate) (TDCSS) monomer. After ring-opening co-polymerization (ROP) of TDCSS and trimethylene carbonate (TMC) initiated by mono-methoxyl poly(ethylene glycol), the crosslinked reduction-sensitive copolymer PEG-P(TMC-co-TDCSS) was obtained via a facile one-step procedure for efficient delivery of doxorubicin (DOX) into cancer cells. To serve as controls, PEG-P(TMC-co-TDCCC), which has an analogous structure without disulfide bond, and a linear polymer PEG-PTMC were also prepared. The copolymers could self-assemble to form nano-sized micelles in an aqueous solution. As compared to PEG-PTMC, crosslinked PEG-P(TMC-co-TDCSS) and PEG-P(TMC-co-TDCCC) showed lower CMC values and thus induced a much better micelle-forming ability. In vitro release studies revealed that the drug release behavior of DOX-loaded PEG-P(TMC-co-TDCSS) micelles, which could be accelerated in the presence of 10 mM dithiothreitol (DTT), showed a similar trend in the absence of DTT compared to DOX-loaded PEG-P(TMC-co-TDCCC) micelles. Furthermore, confocal laser scanning microscopy (CLSM) indicated that DOX-loaded PEG-P(TMC-co-TDCSS) micelles were efficiently internalized into HeLa cells, releasing DOX into the cytoplasm after which the drug finally entered the nuclei, while MTT assays also demonstrated potent cytotoxic activity against HeLa cells. DOX was mainly located in the cytoplasm for reduction-insensitive PEG-P(TMC-co-TDCCC) and PEG-PTMC controls.

Design and construction of self-hidden and pH-reversed targeting drug delivery nanovehicles via noncovalent interactions to overcome drug resistance

Using the host-guest interaction between β-cyclodextrin (β-CD) and adamantane (Ad), and borate formation between phenylboronic acid (PBA) and cis-diols, a smart pH-responsible targeting drug delivery nanovehicle, PBA-PEG-CD/Ad-lys(Diol)-PCL, was prepared via one-step self-assembly. Under physiological conditions, the targeted PBA function could be restrained by binding PBA with diol components located at the interface of self-assemblies, and hydrophilic PEG segments could be shielded simultaneously. When the environmental pH decreased, the PBA groups could be unbound and exposed on the surface of self-assemblies, leading to recovery of its targeted function, as shown using fluorescence spectroscopy, in vitro cell toxicity, and uptake. Under acidic conditions, PBA-PEG-CD/Ad-lys(Diol)-PCL/Dox showed significantly increased uptake and toxicity toward HepG2 cells in comparison with the control group. The smart vehicles were further utilized to test their efficiency in overcoming drug resistance in chemotherapy. Compared with free Dox, PBA-PEG-CD/Ad-lys(Diol)-PCL delivered six times more Dox into MCF-7/ADR cells and showed greater toxicity toward the ADR cells. As a result, this may be a facile strategy toward constructing efficient targeting vehicles through the rational utilization of noncovalent interactions.

Crosslinked self-assemblies of lipoid acid-substituted low molecular weight (1800 Da) polyethylenimine as reductive-sensitive non-viral gene vectors.

In this study, amphiphilic polyethylenimine-graft-thioctic acid (PEI-TA) and polyethylenimine-graft-lauric acid (PEI-LA) were synthesized. Both PEI-TA and PEI-LA could self-assemble into micelles. Due to the existence of disulfide-linked rings at the end of hydrophobic moieties, PEI-TA could form stable micelles with disulfide crosslinked cores (PEI-TA-SS). In comparison with the PEI-LA micelle, PEI-TA-SS possessed higher DNA binding ability according to the gel retardation assay and heparin replacement assay. In vitro transfection experiments indicated that PEI-TA-SS showed comparably high transfection efficiency as compared to 25 kDa PEI. More interestingly, the luciferase expression of PEI-TA-SS was superior to that of PEI-LA at low N/P ratio, which might be ascribed to the stronger binding capacity of PEI-TA-SS facilitating the entering of PEI-TA-SS/pDNA complexes into cells.

Reversible core-crosslinked nanocarriers with pH-modulated targeting and redox-controlled drug release for overcoming drug resistance

Herein, a pH and redox dual-sensitive core-crosslinked targeting nanocarrier was prepared and used for co-delivery of doxorubicin (DOX) and tariquidar (TQR). The nanocarrier not only had excellent stability but also prevented the leakage of the drug in the normal physiological environment efficiently. Meanwhile, the targeting function of nanocarriers could also be suppressed in the normal physiological environment, protecting nanocarriers from being captured by RAW264.7 cells. Under mild acidic conditions, the targeting function was regained, leading to an effective tumor cell uptake of the nanocarrier. Furthermore, reduction-responsive drug release would occur in the cytoplasm due to the collapse of the reduction-sensitive crosslinked structure in the nanocarrier. By means of ligand-receptor mediated endocytosis and TQR-mediated glycoprotein (P-gp) inhibition, the IC50 value of DOX to MCF-7/ADR cells reduced from more than 100 μg mL-1 to 8.55 μg mL-1, exhibiting great potential in overcoming drug resistance.

Design and Construction of a Smart Targeting Drug Delivery System Based on Phototriggered Competition of Host–Guest Interaction

A smart targeting drug delivery nanocarrier is successfully constructed based on phototriggered competition of host-guest interaction. The targeting motif, i.e., biotin is first concealed by β-cyclodextrin (β-CD) via host-guest interaction. When the nanoparticles are exposed to UV light, the cleavage of photosensitive groups results in the exposure of adamantane (Ad) groups initially located in the interior of nanoassemblies, and β-CDs capped on biotin ligands can be replaced by Ad because of the higher binding constant between Ad and β-CD than that between biotin and β-CD. The competition of host-guest interaction leads to the recovery of targeting capacity of biotin ligands on the nanocarriers. By virtue of photoregulation, the nanocarriers exhibit controllable ligand-receptor recognition, which is proved by flow cytometry, laser confocal microscopy, and cytotoxicity assay. This strategy has a potential to improve the selectivity and safety of targeting drug delivery systems.