A novel injectable and high-solid-content drug-loaded supramolecular hydrogel (PTX-mPECT NP/α-CDgel) was prepared by self-assembly of inclusion complexes based on PTX-loaded mPECT (methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-un-decanone)) nanoparticles (PTX-mPECT NPs) and α-cyclodextrin (α-CD). Paclitaxel (PTX) was chosen as a hydrophobic drug encapsulated into mPECT NPs. Then, gelation occurred when the aqueous solution of α-CD was added to the PTX-mPECT NPs aqueous dispersion within several seconds after stirring. Importantly, with the erosion of the hydrogel, PTX-loaded NPs could be released again and then PTX released further. Rheological studies showed that PTX-mPECT NP/α-CDgel with good injectability underwent a shear-induced sol–gel transition. The results of in vitro drug-release studies demonstrated a sustained-release profile, and the cumulative release of PTX was ≈35% after 20 days. The results of cell-uptake studies and in vitro cytotoxicity studies indicated that the PTX-loaded NPs have been efficiently delivered to cells and killed tumor cells. Higher suppression of tumor growth demonstrated the remarkable anticancer effect of PTX-mPECT NP/α-CDgel upon peritumoral injection. These results showed that high-solid-content PTX-mPECT NP/α-CDgel based on in situ systems could be a promising candidate for local and sustained drug delivery.

Finding a smart cancer drug delivery carrier with long blood circulation, enhanced cancer targeting, and quick drug release in tumors is critical for efficient cancer chemotherapy. Herein, we design a cRGD-polycarboxybetaine methacrylate-b-polybenzimidazole methacrylate (cRGD-PCB-b-PBBMZ) copolymer to self-assemble into smart drug-loaded nanoparticles (cRGD-PCM NPs) which can target αvβ3 integrin overexpressed cancer tissue by cRGD peptide unit and release drug quickly in cancer cells by protonation of benzimidazole groups. The outer PCB layer can resist protein adhesion, and there are only about 10% of proteins in mouse serum adhered to the surface of PCM NPs. With the pKa value of 5.08 of the benzimidazole units, DOX can be released from NPs in pH 5.0 PBS. cRGD-PCM NPs can bring more DOX into HepG2 cells than nontargeting PCM NPs, and there has high DOX release rate in HepG2 cells because of the protonation of benzimidazole groups in endosome and lysosome. MTT assay verifies that higher cellular uptake of DOX causes higher cytotoxicity. Furthermore, the results of ex vivo imaging studies confirm that cRGD-PCM/DOX NPs can successfully deliver DOX into tumor tissue from the injection site. Therefore, the multifunctional cRGD-PCM NPs show great potential as novel nanocarriers for targeting cancer chemotherapy.Keywords: benzimidazole; cancer targeting; doxorubicin; nanocarriers; pH-responsive

•A novel thermosensitive hydrogel (PECT).•The introduction of hyaluronic acid. Conduct a process of crosslink between natural polymer (HA) and artificial polymer (PECT).•Self-assembled nanoparticles system.•Realize the tunable properties of hydrogel in some degree.In this work, a new hydrogel was constructed using poly(ɛ-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)–poly(ethylene glycol)–poly(ɛ-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) tri-block copolymers (PECT) with hyaluronic acid (HA) in order to expand application scopes of PECT hydrogel. The rheological and sol–gel phase transition behaviors were investigated by rheometer and test tube inversion method, and the interior morphologies of hydrogel systems were observed by scanning electron microscope (SEM). With the introduction of HA, certain properties of PECT hydrogel, such as viscosity and morphology, have present trends with regularity. Furthermore, with the participation of HA, the degradation and release of acetylsalicylic acid was slightly affected, however, the drug release mechanism of hydrogel has not been changed. PECT/HA hydrogel is confirmed to be non-toxic through a test to NIH3T3 cells. In conclusion, blending with HA is a feasible and safe method to tune properties of PECT hydrogel.

As drug therapies become increasingly sophisticated, the synergistic benefits of two or more drugs are often required. In this study, we aimed at improving anti-tumor efficiency of paclitaxel (PTX)-incorporated thermo-sensitive injectable hydrogel by the synergy of burst release of doxorubicin hydrochloride (DOX⋅HCl). Thermosensitive injectable hydrogel composed of nanoparticles assembled from amphiphilic copolymer poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolaone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) was fabricated. Hydrophobic PTX and hydrophilic DOX⋅HCl were loaded simultaneously in the thermo-sensitive injectable hydrogel by a two-stage entrapment. Thermosensitive gelling behaviors of drug-loading PECT nanoparticle aqueous dispersions were studied. In vitro release profiles of PTX and DOX⋅HCl and in vivo anti-tumor effect by dual drugs from PECT hydrogel were investigated. The results showed that hydrophilic and hydrophobic drugs could be successfully entrapped in PECT hydrogel simultaneously without affecting its thermo-sensitive behavior. In vitro release profiles demonstrated the burst release of DOX⋅HCl and the sustained release of PTX. Anti-tumor effect was improved by a fast and tense attack caused by the burst release of hydrophilic DOX⋅HCl from hydrogel, which was continued by the sequent sustained release of PTX-incorporated nanoparticles and remnant DOX⋅HCl. Unintentionally, entrapped in PECT hydrogel, hydrophilic DOX⋅HCl was observed to have a sustained releasing pattern in vitro and in vivo.Graphical abstractDownload high-res image (104KB)Download full-size image

Thermo-sensitive injectable hydrogels based on poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) block copolymers have attracted considerable attention for sustained drug release and tissue engineering applications. Previously, we have reported a thermo-sensitive hydrogel of P(CL-co-TOSUO)-PEG-P(CL-co-TOSUO) (PECT) triblock copolymers modified by hydrophilic cyclic ether pendant groups 1,4,8-trioxa-[4.6]spiro-9-undecanone (TOSUO). Unfortunately, the low gel modulus of PECT (only 50–70 Pa) may limit its applications. Herein, another kind of thermogelling triblock copolymer of a pendant cyclic ether-modified caprolactonic poloxamer analog, PEG-P(CL-co-TOSUO)-PEG (PECTE), was successfully prepared by control of the hydrophilicity/hydrophobicity balance and chemical compositions of the copolymers. PECTE powder could directly disperse in water to form a stable nanoparticle (NP) aqueous dispersion and underwent sol–gel–sol transition behavior at a higher concentration with the temperature increasing from ambient or lower temperatures. Significantly, the microstructure parameters (e.g., different chemical compositions of the hydrophobic block and topology) played a critical role in the phase transition behavior. Furthermore, comparison studies on PECTE and PEG-PCL-PEG (PECE) showed that the introduction of pendant cyclic ether groups into PCL blocks could avoid unexpected ahead-of-time gelling of the PECE aqueous solution. In addition, the rheological analysis of PECTE and PECT indicated that the storage modulus of the PECTE hydrogel could be 100 times greater than that of the PECT hydrogel under the same mole ratios of TOSUO/CL and lower molecular weight. Consequently, PECTE thermal hydrogel systems are believed to be promising as in situ gel-forming biomaterials for drug delivery and tissue engineering.

A novel injectable and high-solid-content drug-loaded supramolecular hydrogel (PTX-mPECT NP/α-CDgel) was prepared by self-assembly of inclusion complexes based on PTX-loaded mPECT (methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-un-decanone)) nanoparticles (PTX-mPECT NPs) and α-cyclodextrin (α-CD). Paclitaxel (PTX) was chosen as a hydrophobic drug encapsulated into mPECT NPs. Then, gelation occurred when the aqueous solution of α-CD was added to the PTX-mPECT NPs aqueous dispersion within several seconds after stirring. Importantly, with the erosion of the hydrogel, PTX-loaded NPs could be released again and then PTX released further. Rheological studies showed that PTX-mPECT NP/α-CDgel with good injectability underwent a shear-induced sol–gel transition. The results of in vitro drug-release studies demonstrated a sustained-release profile, and the cumulative release of PTX was ≈35% after 20 days. The results of cell-uptake studies and in vitro cytotoxicity studies indicated that the PTX-loaded NPs have been efficiently delivered to cells and killed tumor cells. Higher suppression of tumor growth demonstrated the remarkable anticancer effect of PTX-mPECT NP/α-CDgel upon peritumoral injection. These results showed that high-solid-content PTX-mPECT NP/α-CDgel based on in situ systems could be a promising candidate for local and sustained drug delivery.