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Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of -10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.

Instability of silk fibroin nanoparticles (SFNPs) in physiologic condition hinders its application as drug delivery vehicle. Herein, indocyanine green (ICG) loaded silk fibroin nanoparticles (ICG-SFNPs) was firstly prepared and then crosslinked by proanthocyanidins to obtain the stable ICG-CSFNPs for killing the residual tumour niche under near infra-red irradiation (NIR) after surgery. The particle size and zeta potentials of ICG-CSFNPs was 120.1 nm and -40.4 mV, respectively. Moreover, ICG-CSFNPs exhibited good stability of particle size in the physiological medium. Meanwhile, the stable photothermal properties of ICG-CSFNPs were not compromised even after several cycles of NIR. Few of the ICG-CSFNPs were phagocytized by RAW264.7 macrophage in vitro , while they were easily internalized by C6 glioma cells, resulting in their significant toxicity on tumour cells after NIR. The pharmacokinetic study showed that ICG-CSFNPs had a longer blood circulation time than ICG-SFNPs, making them more distribution in glioma after intravenous administration in vivo . Meanwhile, the pharmacological study showed the more effective inhibition of tumour growth was exhibited by ICG-CSFNPs in C6 glioma-bearing mice after NIR. Overall, the cross-linked nanoparticles of silk fibroin may be a promising vehicle of ICG for photothermal therapy of glioma after surgical resection.

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from d-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core-shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8 nm and a zeta-potential of -30.5 mV, while its core-shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties.

Silk was easily dyed in traditional textile industry because of its strong affinity to many colorants. Herein, the biocompatible silk fibroin was firstly extracted from Bombyx mori silkworm cocoons. And SF nanoparticles (SFNPs) were prepared for dyeing indocyanine green (ICG) and construct a therapeutic nano-platform (ICG-SFNPs) for photo-thermal therapy of glioblastoma. ICG was easily encapsulated into SFNPs with a very high encapsulation efficiency reaching to 97.7 ± 1.1%. ICG-SFNPs exhibited a spherical morphology with a mean particle size of 209.4 ± 1.4 nm and a negative zeta potential of -31.9 mV, exhibiting a good stability in physiological medium. Moreover, ICG-SFNPs showed a slow release profile of ICG in vitro, and only 24.51 ± 2.27% of the encapsulated ICG was released even at 72 h. Meanwhile, ICG-SFNPs exhibited a more stable photo-thermal effect than free ICG after exposure to near-infrared irradiation. The temperature of ICG-SFNPs rapidly increased by 33.9 °C within 10 min and maintained for a longer time. ICG-SFNPs were also easily internalized with C 6 tumor cells in vitro, and a strong red fluorescence of ICG was observed in cytoplasm for cellular imaging. In vivo imaging showed that ICG-SFNPs were effectively accumulated inside tumor site of C 6 glioma-bearing Xenograft nude mice through vein injection. Moreover, the temperature of tumor site was rapidly rising up to kill tumor cells after local NIR irradiation. After treatment, its growth was completely suppressed with the relative tumor volume of 0.55 ± 033 while free ICG of 33.72 ± 1.90. Overall, ICG-SFNPs may be an effective therapeutic means for intraoperative phototherapy and imaging.

Most breast tumours are heterogeneous and not only contain the bulk of differentiated tumour cells but also a small population of highly tumorigenic and intrinsically drug-resistant cancer stem cells (CSCs). Herein, a pH-sensitive nanoparticle with simultaneous encapsulation of curcumin and doxorubicin (CURDOX-NPs) was prepared by using monomethoxy (polyethylene glycol)-b-P (D,L-lactic-co-glycolic acid)-b-P (L-glutamic acid) polymer to simultaneously target the differentiated tumor cells and CSCs. CURDOX-NPs had a mean diameter of 107.5 nm and zeta potential of -13.7 mV, determined by DLS. Drug-loading efficiency for curcumin and doxorubicin was reaching to 80.30% and 96.2%, respectively. Moreover, a cascade sustained-release profiles with the faster release of CUR followed by a slower release of DOX was observed in normal pH7.4 condition. Moreover, a pH-sensitive release profile for each cargo was seen in pH5.0 condition. The anti-tumour effect of CURDOX-NPs on CSCs-enriching MCF-7/ADR mammospheres was confirmed by in vitro. Moreover, a significant regression of tumour growth after treatment with CURDOX-NPs was also observed in Xenograft mice model. The percentage of CSCs in tumour significantly decreased from 39.9% in control group to 6.82% after treatment with CURDOX-NPs. The combinational delivery of CUR and DOX may a potentially useful therapeutic strategy for refractory breast cancer.

A poor percutaneous penetration capability for most topical anti-inflammatory drugs is one of the main causes compromising their therapeutic effects on psoriatic skin. Even though curcumin has shown a remarkable efficacy in the treatment of psoriasis, its effective penetration through the stratum corneum is still a major challenge during transdermal delivery. The aim of our study was to design skin-permeating nanoparticles (NPs) to facilitate delivery of curcumin to the deeper layers of the skin. A novel amphiphilic polymer, RRR-α-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL) was synthesized and self-assembled into polymeric nanoparticles. The nanoparticles of VES-g-ε-PLL exhibiting an ultra-small hydrodynamic diameter (24.4nm) and a positive Zeta potential (19.6mV) provided a strong skin-penetrating ability in vivo. Moreover, curcumin could effectively be encapsulated in the polymeric nanoparticles with a drug loading capacity of 3.49% and an encapsulating efficiency of 78.45%. In order to prolong the retention time of the ultra-small curcumin-loaded nanoparticles (CUR-NPs) in the skin, silk fibroin was used as a hydrogel-based matrix to further facilitate topical delivery of the model drug. In vitro studies showed that CUR-NPs incorporated in silk fibroin hydrogel (CUR-NPs-gel) exhibited a slower release profile of curcumin than the plain CUR-gel, without compromising the skin penetration ability of CUR-NPs. In vivo studies on miquimod-induced psoriatic mice showed that CUR-NPs-gel exhibited a higher therapeutic effect than CUR-NPs as the former demonstrated a more powerful skin-permeating capability and a more effective anti-keratinization process. CUR-NPs-gel was therefore able to inhibit the expression of inflammatory cytokines (TNF-α, NF-κB and IL-6) to a greater extent. In conclusion, the permeable nanoparticle-gel system may be a potential carrier for the topical delivery of lipophilic anti-psoriatic drugs., (Copyright © 2017. Published by Elsevier B.V.)

The present study seeks to observe the preventive effects of doxorubicin-induced cardiomyopathy (DOX-CM) in rats using targeted non-mitogenic acidic fibroblast growth factor (MaFGF) mediated by nanoparticles (NP) combined with ultrasound-targeted MB destruction (UTMD). DOX-CM rats were induced by intraperitoneally injected doxorubicin. Six weeks after intervention, the indices from the transthoracic echocardiography and velocity vector imaging showed that the left ventricular function in the MaFGF-loaded NP (MaFGF-NP) + UTMD group was significantly improved compared with the DOX-CM group. The increased malondialdehyde and decreased superoxide dismutase were observed in the DOX-CM group, while a significant increase in superoxide dismutase and a decrease in malondialdehyde were detected in the groups treated with MaFGF-NP + UTMD. From the Masson staining, the MaFGF-NP + UTMD group showed a significant difference from the DOX-CM group. The cardiac collagen volume fraction and the ratio of the perivascular collagen area to the luminal area number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling positive cells in the MaFGF-NP + UTMD group decreased to 8.9%, 0.55-fold, compared with the DOX-CM group (26.5%, 1.7-fold). From terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling staining, the results showed the strongest inhibition of apoptosis progress in MaFGF-NP + UTMD group. The immunohistochemical staining of the TGF-β1 in MaFGF-NP + UTMD group reached 3.6%, which was much lower than that of the DOX-CM group (12.6%). These results confirmed that the abnormalities, including left ventricular dysfunction, myocardial fibrosis, cardiomyocytes apoptosis and oxidative stress, could be suppressed by twice weekly MaFGF treatments for 6 consecutive weeks (free MaFGF or MaFGF-NP+/UTMD), with the strongest improvements observed in the MaFGF-NP + UTMD group. Western blot analyses of the heart tissue further revealed the highest pAkt levels, highest anti-apoptosis protein (Bcl-2) levels and strongest reduction in proapoptosis protein (Bax) levels in the MaFGF-NP + UTMD group. This study confirmed the preventive effects of DOX-CM in the rats with MaFGF-NP and UTMD by retarding myocardial fibrosis, inhibiting oxidative stress, and decreasing cardiomyocyte apoptosis., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Malignant gliomas especially glioblastoma (GBM) are poorly responsive to the current treatments. Cilengitide (CGT) is a cyclic pentapeptide that demonstrated efficacy for GBM treatment by targeting the integrins a v β 3 and a v β 5 over-expressed on GBM cells. However, clinical translation of this therapy has been limited by issues including fast blood clearance, high kidney and liver uptake, poor blood–brain barrier (BBB) penetration, low tumor specificity and rapid washout from tumors. In this study, these issues were tackled in an integrated manner using a multi-stage strategy combining ultrasound-targeted microbubble destruction (UTMD) with CGT nanotherapy. CGT nanoparticles (CGT-NP) prepared using gelatin and Poloxamer 188-grafted heparin copolymer demonstrated significant apoptotic and cytotoxic effects in C6 GBM cells. Biodistribution study in a rat GBM model demonstrated buildup of high CGT level in tumors subjected to CGT-NP + UTMD combined therapy. The tumor CGT level in these animals was increased over 3-fold, tumor retention of CGT prolonged and renal clearance significantly reduced when compared with free CGT with or without UTMD. CGT-NP + UTMD treatment was further shown to extend the median survival period from less than 20 days in the control and about 30 days in free CGT group to about 80 days. This was achieved with low CGT dosing level (2 mg/kg twice weekly). In situ monitoring of GFAP, Ki67, caspase-3, Beclin-1, and LC-3 in the tumor samples together with TUNEL assay, transmission electron microscope imaging and Western blot assay all demonstrated high apoptotic and autophagy activities induced by the combined therapy. In conclusion, this study has provided extensive preclinical data supporting the use of this combined therapy to overcome the limitations of standard CGT treatment of gliomas. [ABSTRACT FROM AUTHOR]