Cisplatin-directed coordination-crosslinking nanogels with thermo/pH-sensitive triblock polymers: improvement on chemotherapic efficacy via sustained release and drug retention.

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.

The studies about doxorubicin-loaded p(N-isopropyl-acrylamide-co-butyl methylacrylate) temperature-sensitive nanogel dispersions on the application in TACE therapies for rabbit VX2 liver tumor.

Transarterial chemo-embolization (TACE), which combined embolization therapy and chemotherapy, has become the most widely used treatment for unresectable liver cancer. Blood-vessel-embolic materials play key role on TACE. In the present work, doxorubicin-loaded p(N-isopropylacrylamide-co-butyl methylacrylate) nanogels-iohexol dispersions (IBi-D) were reported firstly for TACE therapy to liver cancer. Using inverting-vial method, IBi-D dispersions showed three phases (swollen gel, flowable sol and shrunken gel) as temperature increased. Although Dox had little effect on the CGTs between flowable and shrunken gel, the rheological properties of IBi-D dispersions could greatly improved by Dox. A sustained Dox-release, which was necessary in TACE therapy, was found from IBi-D dispersions in the eluting medium of PBS buffers. The studies about renal artery embolization of normal rabbits indicated that IBi-D dispersions showed good properties in embolizing all kinds of renal arteries (including peripheral, small and large arteries) by controlling their injecting dosages. Angiography and medical evaluation indicated that TACE therapy of IBi-D dispersions has better efficacy on rabbit VX2 liver tumors than TAC treatment of free Dox and TAE treatment of IBi dispersions.