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.

In the present study, we prepared a multi-drug delivery system based on reduction-sensitive paclitaxel (PTX) polymeric prodrug(PEG-b-PMPMC-g-PTX, PMP) polymersomes to co-deliver PTX, doxorubicin hydrochloride(DOX·HCl) and the P-glycoprotein(P-gp) inhibitor Tariquidar(TQR) to effectively reverse drug resistance by inhibiting the expression of P-gp and improving the accumulation of the encapsulated anticancer drugs. The PTX was linked to the backbone by reduction-sensitive disulphide, making the polymersomes prone to collapse in the reductive environment and to release the drugs. Transmission electron microscope(TEM) was used to confirm the morphology of polymeric assemblies. Moreover, the rupture process of polymersomes was verified by dynamic light scattering (DLS). The results of confocal laser scanning microscopy(CLSM) and flow cytometry indicate that the PMP/DOX·HCl/TQR three-drug-loaded polymersomes show the strongest fluorescence intensity for DOX·HCl compared with PMP/DOX·HCl polymersomes and free DOX·HCl in drug-resistant MCF-7/ADR cells. More importantly, the PMP/DOX·HCl/TQR multi-drug co-delivery system shows a greater growth-inhibitory effect on tumour cells than the other two samples, including PMP/DOX·HCl nanoparticles without the TQR component and free DOX·HCl, when co-incubated with either nonresistant HeLa cells or drug-resistant MCF-7/ADR cells. This growth-inhibitory effect was especially evident in drug-resistant cells. These results imply that the co-delivery of PTX, DOX·HCl and TQR based on reduction-sensitive polymeric prodrug may be promising for overcoming multi-drug resistance in tumour treatments.

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.

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.

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.

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.