Doxorubicin (DOX), a kind of wide-spectrum chemotherapeutic drug, can cause severe side effects in clinical use. To enhance its antitumor efficacy while reducing the side effects, two kinds of nanoparticles with desirable compositions and properties were assembled using optimally synthesized hydroxyethyl starch-grafted-polylactide (HES-g-PLA) copolymers and utilized as partner nanocarriers. The large empty HES-g-PLA nanoparticles (mean size, ca. 700 nm), at an optimized dose of 400 mg/kg, were used to block up the reticuloendothelial system in tumor-bearing mice 1.5 h in advance, and the small DOX-loaded HES-g-PLA nanoparticles (mean size, ca. 130 nm) were subsequently applied to the mice. When these partner nanocarriers were administered in this sequential mode, the released DOX had a significantly prolonged plasma half-life time and much slower clearance rate as well as a largely enhanced intratumoral accumulation as compared to free DOX. In vivo antitumor studies demonstrated that the DOX-loaded HES-g-PLA nanoparticles working together with their partner exhibited remarkably enhanced antitumor efficacy in comparison to free DOX. In addition, these HES-g-PLA partner nanocarriers showed negligible damage to the normal organs of the treated mice. Considering safe and efficient antitumor performance of DOX-loaded HES-g-PLA nanoparticles, the newly developed partner nanocarriers in combination with their administration mode have promising potential in clinical cancer chemotherapy.Keywords: cancer chemotherapy; doxorubicin; hydroxyethyl starch copolymer; nanoparticle; partner carrier; polylactide;

Paclitaxel (PTX) is an effective antineoplastic agent and shows potent antitumor activity against a wide spectrum of cancers. Yet, the wide clinical use of PTX is limited by its poor aqueous solubility and the side effects associated with its current therapeutic formulation. To tackle these obstacles, we report, for the first time, α-amylase- and redox-responsive nanoparticles based on hydroxyethyl starch (HES) for the tumor-targeted delivery of PTX. PTX is conjugated onto HES by a redox-sensitive disulfide bond to form HES–SS-PTX, which was confirmed by results from NMR, high-performance liquid chromatography-mass spectrometry, and Fourier transform infrared spectrometry. The HES–SS-PTX conjugates assemble into stable and monodispersed nanoparticles (NPs), as characterized with Dynamic light scattering, transmission electron microscopy, and atomic force microscopy. In blood, α-amylase will degrade the HES shell and thus decrease the size of the HES–SS-PTX NPs, facilitating NP extravasation and penetration into the tumor. A pharmacokinetic study demonstrated that the HES–SS-PTX NPs have a longer half-life than that of the commercial PTX formulation (Taxol). As a consequence, HES–SS-PTX NPs accumulate more in the tumor compared with the extent of Taxol, as shown in an in vivo imaging study. Under reductive conditions, the HES–SS-PTX NPs could disassemble quickly as evidenced by their triggered collapse, burst drug release, and enhanced cytotoxicity against 4T1 tumor cells in the presence of a reducing agent. Collectively, the HES–SS-PTX NPs show improved in vivo antitumor efficacy (63.6 vs 52.4%) and reduced toxicity in 4T1 tumor-bearing mice compared with those of Taxol. These results highlight the advantages of HES-based α-amylase- and redox-responsive NPs, showing their great clinical translation potential for cancer chemotherapy.Keywords: dual stimuli-responsive nanoparticles; hydroxyethyl starch; redox-responsive; targeted cancer chemotherapy; α-amylase-responsive;

Selective drug release is highly desirable for photothermal/chemo combination therapy when two or even more theranostic agents are encapsulated together within the same nanocarrier. A conventional nanocarrier can hardly achieve this goal. Herein, doxorubicin and indocyanine green (DOX/ICG)-loaded nanocolloidosomes (NCs), with selective drug release, were fabricated as a novel multifunctional theranostic nanoplatform for photothermal/chemo combination therapy. Templating from galactose-functionalized hydroxyethyl starch-polycaprolactone (Gal-HES-PCL) nanoparticles-stabilized Pickering emulsions, the resultant DOX/ICG@Gal-HES-PCL NCs had a diameter of around 140 nm and showed an outstanding tumor-targeting ability, preferable tumor penetration capability, and promotion of photothermal effect. Moreover, these NCs can be used for NIR fluorescence imaging and thus render real-time imaging of solid tumors with high contrast. Collectively, such NCs achieved the best in vivo antitumor efficacy combined with laser irradiation compared with DOX/ICG@HES-PCL NCs and DOX/ICG mixture. These NCs are valuable for active tumor-targeted imaging-guided combination therapy against liver cancer and potentially other diseases.Keywords: active targeting; hydroxyethyl starch; nanocolloidosomes; photothermal/chemo combination therapy; selective drug release;

To realize the sustained release and long-term intratumoural retention of water-soluble cisplatin, thermo/pH-sensitive cisplatin-directed coordination-crosslinking nanogels (Pt-PNA) were developed via the coordination bonds of Pt–carboxyl groups. As the coordination ratio (CR) of the Pt–carboxyl bonds increased from 5% to 35%, the sizes of the Pt-PNA nanogels decreased from 999 nm to 167 nm, and their zeta potentials increased from −35 mV to −13 mV. Only through a simple mixing of cisplatin and PNAs, the entrapment efficiencies (EEs) of the Pt-PNA nanogels reached near 100% (>90%), and the drug-loading amounts (DLs) of cisplatin could achieve up to 25.5 ± 0.1%. For water-soluble cisplatin, Pt-PNA nanogels exhibited a sustained release for as long as 5 days. The thermo/pH-sensitive sol–gel phase-transition behaviour of the Pt-PNA nanogels were investigated via inverting-vial and rheological methods. Platinum elemental analysis indicated that the Pt-PNA nanogels showed a much stronger ability of cisplatin retention in tumours than free cisplatin. The platinum content in a tumour treated by the Pt-PNA nanogels was far higher than that by free cisplatin: 200.7 ± 63.6 μg vs. 82.7 ± 26.8 μg at the 1st day, or 118.9 ± 35.2 μg vs. 18.5 ± 9.4 μg at the 14th day. The evaluation of the in vivo antitumour efficacy indicated that only after a single dose of Pt-PNA nanogels, the tumour volume continuously decreased to 0.73 ± 0.07 times that of the original tumour volume (OTV) for 14 days; however, it rapidly increased by 3.37 ± 0.82, 8.01 ± 0.53 and 9.25 ± 1.85 times that of the OTV with the same dose of free cisplatin, PNA, and NS, respectively. Some preliminary evaluations of the biocompatibility indicated that the toxic side effects of cisplatin could be greatly improved via cisplatin-directed coordination-crosslinking with PNA. As a result, Pt-PNA nanogels could likely become a promising versatile strategy for improving antitumour efficacy and reducing the toxicity and size effects of platinum-based drugs, and they could also be developed as promising nanomedicines for regional chemotherapy.

Temperature sensitive p(N-isopropylacrylamide-co-acrylic acid) modified gold nanoparticles (GNP@PNA) were prepared via coordination bonding between gold and sulfur elements. Their diameter and zeta potential were 86 nm and −26.2 mV at 25 °C, and 47 nm and −30.5 mV at 37 °C respectively. Thermogravimetric characterization of GNP@PNA indicated that the PNA shell and the GNP core accounted for 19.2 wt% and 78.2 wt%, namely ca. 70–80 chains of PNA were combined on the surface of one GNP nanoparticle. GNP@PNA showed much better X-ray attenuation ability, ca. 1.6–3.3 times higher than that of Omnipaque. In addition, the temperature sensitive sol–gel transition of GNP@PNA dispersions could realize the so-called “in situ casting” embolization from tumoral aorta to peripheral arteries, and improve their angiographic ability owing to the inhibition against GNP aggregation via gelation. Renal artery embolization on normal rabbits and TAE on VX2 tumor-bearing rabbits indicated that GNP@PNA achieved better embolization for longer times than Ivalon and Lipiodol. Excellent biocompatibility of GNP@PNA dispersions was also observed via the evaluation of cytotoxicity, hemolysis and hepatorenal function.

Doxorubicin (DOX)-induced co-assembling nanomedicines (D-PNAx) with temperature-sensitive PNAx triblock polymers have been developed for regional chemotherapy against liver cancer via intratumoral administration in the present work. Owing to the formation of insoluble DOX carboxylate, D-PNAx nanomedicines showed high drug-loading and entrapment efficacy via a simple mixing of doxorubicin hydrochloride and PNAx polymers. The sustained releasing profile of D-PNA100 nanomedicines indicated that only 9.4% of DOX was released within 1 day, and 60% was released during 10 days. Based on DOX-induced co-assembling behavior and their temperature sensitive in-situ-forming hydrogels, D-PNA100 nanomedicines showed excellent antitumor activity against H22 tumor using intratumoral administration. In contrast to that by free DOX solution (1.13 ± 0.04 times at 9 days) and blank PNA100 (2.11 ± 0.34 times), the tumor volume treated by D-PNA100 had been falling to only 0.77 ± 0.13 times of original tumor volume throughout the experimental period. In vivo biodistribution of DOX indicated that D-PNA100 nanomedicines exhibited much stronger DOX retention in tumor tissues than free DOX solution via intratumoral injection. D-PNA100 nanomedicines were hopeful to be developed as new temperature sensitive in-situ-forming hydrogels via i.t. injection for regional chemotherapy.D-PNA100 nanomedicines are co-assembled by mixing PNA100 and doxorubicin hydrocloride (DOX·HCl). The co-assembly, along with temperature-sensitive sol–gel transition, play important role on prolonging retention time in tumor.

Doxorubicin (DOX) is one of the most potent anticancer agents in cancer chemotherapy, but the clinical use of DOX is restricted by its severe side effects caused by nonspecific delivery. To alleviate the side effects and improve the antitumor efficacy of DOX, a novel redox-sensitive hydroxyethyl starch–doxorubicin conjugate, HES-SS-DOX, with diameter of 19.9 ± 0.4 nm was successfully prepared for tumor targeted drug delivery and GSH-mediated intracellular drug release. HES-SS-DOX was relatively stable under extracellular GSH level (∼2 μM) but released DOX quickly under intracellular GSH level (2–10 mM). In vitro cell study confirmed the GSH-mediated cytotoxicity of HES-SS-DOX. HES-SS-DOX exhibited prolonged plasma half-life time and enhanced tumor accumulation in comparison to free DOX. As a consequence, HES-SS-DOX exhibited better antitumor efficacy and reduced toxicity as compared to free DOX in the in vivo antitumor activity study. The redox-sensitive HES-SS-DOX was proved to be a promising prodrug of DOX, with clinical potentials, to achieve tumor targeted drug delivery and timely intracellular drug release for effective and safe cancer chemotherapy.Keywords: chemotherapy; conjugate; doxorubicin; hydroxyethyl starch; redox-sensitive; tumor targeted drug delivery

A novel kind of star triptycene-based microporous polymer (STPs) was synthesized efficiently from trihalotriptycenes by nickel(0)-catalyzed Ullmann cross-coupling reactions. STPs display a BET surface area of 1305 m2 g–1 and 1990 m2 g–1, and reversibly adsorb 1.60 and 1.93 wt % H2 at 1.0 bar/77 K, 16.15 and 18.20 wt % CO2 at 1.0 bar/273 K for STP-I and STP-II, respectively.

Temperature sensitive p(N-isopropylacrylamide-co-acrylic acid) modified gold nanoparticles (GNP@PNA) were prepared via coordination bonding between gold and sulfur elements. Their diameter and zeta potential were 86 nm and −26.2 mV at 25 °C, and 47 nm and −30.5 mV at 37 °C respectively. Thermogravimetric characterization of GNP@PNA indicated that the PNA shell and the GNP core accounted for 19.2 wt% and 78.2 wt%, namely ca. 70–80 chains of PNA were combined on the surface of one GNP nanoparticle. GNP@PNA showed much better X-ray attenuation ability, ca. 1.6–3.3 times higher than that of Omnipaque. In addition, the temperature sensitive sol–gel transition of GNP@PNA dispersions could realize the so-called “in situ casting” embolization from tumoral aorta to peripheral arteries, and improve their angiographic ability owing to the inhibition against GNP aggregation via gelation. Renal artery embolization on normal rabbits and TAE on VX2 tumor-bearing rabbits indicated that GNP@PNA achieved better embolization for longer times than Ivalon and Lipiodol. Excellent biocompatibility of GNP@PNA dispersions was also observed via the evaluation of cytotoxicity, hemolysis and hepatorenal function.