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Chemotherapy is an important modality in cancer treatment. The major challenge of recent works in this research field is to develop new types of smart nanocarriers that can respond selectively to cancer cell-specific conditions and realize rapid drug release in target cells. In the present study, a reactive oxygen species-responsive nanocarrier has been successfully self-assembled from an amphiphilic hyperbranched polymer consisting of alternative hydrophobic selenide groups and hydrophilic phosphate segments in the dendritic backbone. Because the hydrophobic selenide groups transformed into the hydrophilic selenone groups after oxidation under the exclusive oxidative microenvironment within cancer cells, the amphiphilic hyperbranched precursors become hydrophilic ones. As a result, the nanocarriers were rapidly disassembled in target cells, resulting in fast intracellular drug release. The hydrophilic products of oxidation can be degraded into harmless small molecular species via the enzymatic digestion of the phosphate segments and then eliminated by renal excretion. Meanwhile, the reactive selenium-containing nanocarrier possesses a potent intrinsic anticancer effect since selenium compounds can produce antitumor metabolites which induce apoptosis of cancer cells efficiently. Therefore, this type of therapeutic nanocarriers with a unique drug release mechanism based on an amphiphilic-to-hydrophilic transition provides a new platform for targeted drug delivery and combined therapy.

Novel redox-responsive polyphosphate nanosized assemblies based on amphiphilic hyperbranched multiarm copolyphosphates (HPHSEP-star-PEP(x)) with backbone redox-responsive, good biocompatibility, and biodegradability simultaneously have been designed and prepared successfully. The hydrophobic core and hydrophilic multiarm of HPHSEP-star-PEP(x) are composed of hyperbranched and linear polyphosphates, respectively. Benefiting from the amphiphilicity, HPHSEP-star-PEP(x) can self-assemble into spherical micellar nanoparticles in aqueous media with tunable size from about 70 to 100 nm via adjusting the molecular weight of PEP multiarm. Moreover, HPHSEP-star-PEP(x) micellar structure can be destructed under reductive environment and result in a triggered drug release behavior. The glutathione-mediated intracellular drug delivery was investigated against a HeLa human cervical carcinoma cell line, and the results indicate that doxorubicin-loaded (DOX-loaded) HPHSEP-star-PEP(x) micelles show higher cellular proliferation inhibition against glutathione monoester pretreated HeLa cells than that of the nonpretreated ones. In contrast, the DOX-loaded micelles exhibit lower inhibition against buthionine sulfoximine pretreated HeLa cells. These results suggest that such redox-responsive polyphosphate micelles can rapidly deliver anticancer drugs into the nuclei of tumor cells enhancing the inhibition of cell proliferation and provide a favorable platform to construct excellent drug delivery systems for cancer therapy.

Novel supramolecular copolymer micelles with stimuli-responsive abilities were successfully prepared through the complementary multiple hydrogen bonds of nucleobases and then applied for rapid intracellular release of drugs. First, both adenine-terminated poly(ε-caprolactone) (PCL-A) and uracil-terminated poly(ethylene glycol) (PEG-U) were synthesized. The supramolecular amphiphilic block copolymers (PCL-A:U-PEG) were formed based on multiple hydrogen bonding interactions between PCL-A and PEG-U. The micelles self-assembled from PCL-A:U-PEG were sufficiently stable in water but prone to fast aggregation in acidic condition due to the dynamic and sensitive nature of noncovalent interactions. The low cytotoxicity of supramolecular copolymer micelles was confirmed by MTT assay against NIH/3T3 normal cells. As a hydrophobic anticancer model drug, doxorubicin (DOX) was encapsulated into these supramolecular copolymer micelles. In vitro release studies demonstrated that the release of DOX from micelles was significantly faster at mildly acid pH of 5.0 compared to physiological pH. MTT assay against HeLa cancer cells showed DOX-loaded micelles had high anticancer efficacy. Hence, these supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases are very promising candidates for rapid controlled release of drugs.

A water-soluble hyperbranched polyphosphate (HPHEEP) was synthesized through the self-condensation ring-opening polymerization (SCROP) of 2-(2-hydroxyethoxy)ethoxy-2-oxo-1,3,2-dioxaphospholane (HEEP), and its suitability as a drug carrier was then evaluated in vitro. Methyl tetrazolium (MTT) and live/dead staining assays indicated that HPHEEP had excellent biocompatibility against COS-7 cells. The good biodegradability of HPHEEP was observed by NMR analysis, and the degradation products were nontoxic to COS-7 cells. Flow cytometry and confocal laser scanning microscopy analyses suggested that HPHEEP could be easily internalized by vivid cells and preferentially accumulated in the perinuclear region. Furthermore, a hydrophobic anticancer drug, chlorambucil, was used as a model drug and covalently bound to HPHEEP. The chlorambucil dose of the conjugate and free drug required for 50% cellular growth inhibition were 75 and 50 microg/mL, respectively, according to MTT assay against an MCF-7 breast cancer cell line in vitro. This high activity of the conjugate may be attributed to the biodegradability of HPHEEP so as to release the chlorambucil in cells. Therefore, on the basis of its biocompatibility and biodegradability, HPHEEP could provide a charming opportunity to design some excellent drug delivery systems for therapeutic applications.

Novel cationic drug carriers based on hyperbranched poly(amine-ester)s were successfully prepared through proton-transfer polymerization. Both vinyl and epoxy groups of commercially available glycidyl methacrylate monomer could be polymerized through oxyanionic initiation of triethanolamine in the presence of potassium hydride catalysis. By changing the molar ratios of triethanolamine/glycidyl methacrylate or potassium hydride/triethanolamine, we obtained a series of hyperbranched poly(amine-ester)s. The generation of highly branched poly(amine-ester)s was confirmed by (13)C DEPT-135 NMR and 2D NMR techniques, and their degrees of branching were found to be 0.47 to 0.68. The structure and properties of hyperbranched poly(amine-ester)s were analyzed by dynamic light scattering, gel permeation chromatography, Fourier transformed infrared, differential scanning calorimeter, and zeta-potential measurements. Methyl tetrazolium (MTT) assay suggested that the cell viability after 48 h incubation with hyperbranched poly(amine-ester) concentrations up to 1 mg/mL remained nearly 100% compared with the untreated cells. The high cellular uptake of these cationic polymers was confirmed by flow cytometry and confocal laser scanning microscopy. Furthermore, conjugation of a model hydrophobic anticancer drug chlorambucil to hyperbranched poly(amine-ester)s inhibited the proliferation of MCF-7 breast cancer cells. MTT assay indicated that the chlorambucil dose required for 50% cellular growth inhibition against MCF-7 cells was 120 microg/mL. All of these results show that hyperbranched poly(amine-ester)s are promising materials for drug delivery.

Biodegradable hyperbranched polyglycerols (dHPGs) were synthesized through oxyanionic initiating hybrid polymerization of glycerol and glycidyl methacrylate. Due to the introduction of ester linkages into the hyperbranched polyglycerol backbone, dHPGs showed good biodegradability and low cytotoxicity. Benefiting from the existence of terminal hydroxyls and methacryloyl groups, both the anticancer drug methotrexate (MTX) and fluorescent probe Rhodamine-123 could be conjugated onto the surface of dHPGs easily. The resultant MTX-conjugated polymers (dHPG-MTXs) exhibited an amphiphilic character, resulting in the formation of micelles in an aqueous solution. The release of MTX from micelles was significantly faster at mildly acidic pH of 5.0 compared to physiological pH of 7.4. dHPG-MTX micelles could be efficiently internalized by cancer cells. MTT assay against cancer cells showed dHPG-MTXs micelles had high anticancer efficacy. On the basis of their good biodegradability and low cytotoxicity, dHPGs provide an opportunity to design excellent drug delivery systems.

Oxime bonds dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their own niche. In the present work, oxime linkages were confirmed to be a robust tool for the design of pH-sensitive polymeric drug delivery systems. The triblock copolymer (PEG-OPCL-PEG) consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic oxime-tethered polycaprolactone (OPCL) was successfully prepared by aminooxy terminals of OPCL ligating with aldehyde-terminated PEG (PEG-CHO). Owing to its amphiphilic architecture, PEG-OPCL-PEG self-assembled into the micelles in aqueous media, validated by the measurement of critical micelle concentration (CMC). The MTT assay showed that PEG-OPCL-PEG exhibited low cytotoxicity against NIH/3T3 normal cells. Doxorubicin (DOX) as a model drug was encapsulated into the PEG-OPCL-PEG micelles. Drug release study revealed that the DOX release from micelles was significantly accelerated at mildly acid pH of 5.0 compared to physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery systems with oxime linkages. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. MTT assay against HeLa cancer cells showed DOX-loaded PEG-OPCL-PEG micelles had a high anticancer efficacy. All of these results demonstrate that these polymeric micelles self-assembled from oxime-tethered block copolymers are promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs.

The hydrophobic block of polymeric micelles formed by amphiphilic copolymers has no direct therapeutical effect, and the metabolites of these hydrophobic segments might lead to some unexpected side effects. Here the hydrophobic core of polymeric micelles is replaced by highly water-insoluble drugs themselves, forming a new micellar drug delivery system. By grafting hydrophobic drugs of paclitaxel (PTX) onto the surface of hydrophilic hyperbranched poly(ether-ester) (HPEE), we constructed an amphiphilic copolymer (HPEE-PTX). HPEE-PTX could self-assemble into micellar nanoparticles in aqueous solution with tunable drug contents from 4.1 to 10.7%. Moreover, the hydrolysis of HPEE-PTX in serum resulted in the cumulative release of PTX. In vivo evaluation indicated that the dosage toleration of PTX in mice had been improved greatly and HPEE-PTX micellar nanoparticles could be used as an efficient prodrug with satisfactory therapeutical effect. We believe that most of the lipophilic drugs could improve their characters through this strategy.

A new type of biodegradable micelles for glutathione-mediated intracellular drug delivery was developed on the basis of an amphiphilic hyperbranched multiarm copolymer (H40-star-PLA-SS-PEP) with disulfide linkages between the hydrophobic polyester core and hydrophilic polyphosphate arms. The resulting copolymers were characterized by nuclear magnetic resonance (NMR), Fourier transformed infrared (FTIR), gel permeation chromatography (GPC), and differential scanning calorimeter (DSC) techniques. Benefiting from amphiphilic structure, H40-star-PLA-SS-PEP was able to self-assemble into micelles in aqueous solution with an average diameter of 70 nm. Moreover, the hydrophilic polyphosphate shell of these micelles could be detached under reduction-stimulus by in vitro evaluation, which resulted in a rapid drug release due to the destruction of micelle structure. The glutathione-mediated intracellular drug delivery was investigated against a Hela human cervical carcinoma cell line. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements demonstrated that H40-star-PLA-SS-PEP micelles exhibited a faster drug release in glutathione monoester (GSH-OEt) pretreated Hela cells than that in the nonpretreated cells. Cytotoxicity assay of the doxorubicin-loaded (DOX-loaded) micelles indicated the higher cellular proliferation inhibition against 10 mM of GSH-OEt pretreated Hela cells than that of the nonpretreated ones. As expected, the DOX-loaded micelles showed lower inhibition against 0.1 mM of buthionine sulfoximine (BSO) pretreated Hela cells. These reduction-responsive and biodegradable micelles show a potential to improve the antitumor efficacy of hydrophobic chemotherapeutic drugs.