Ratiometric delivery of two therapeutic candidates with inherently dissimilar physicochemical property through pH-sensitive core-shell nanoparticles targeting the heterogeneous tumor cells of glioma.

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.

CoQ10-loaded liposomes combined with UTMD prevented early nephropathy of diabetic rats.

Nephropathy is one of the most severe complications of diabetic patients. The therapeutic strategies for diabetic patients should not only focus on the control of blood glucose but also pay attention to the occurrence of diabetic nephropathy (DN). Coenzyme Q10 (CoQ10) has great therapeutic potential for DN. However, the clinical application of CoQ10 has been limited because of its low water-solubility and non-specific distribution. Liposomes were supposed to be an effective way for delivering CoQ10 to kidney. CoQ10 was effectively encapsulated into the liposome (CoQ10-LIP) with a high entrapment efficiency of 86.15 %. The CoQ10-LIP exhibited a small hydrodynamic diameter (180 ± 2.1 nm) and negative zeta potential (-18.20 mV). Moreover, CoQ10-LIP was combined with ultrasound-mediated microbubble destruction (UTMD) to enhance specific distribution of CoQ10 in kidney. In early stage of diabetic mellitus (DM), rats were administrated with CoQ10-LIP followed by UTMD (CoQ10-LIP+UTMD) to prevent occurrence of DN. Results revealed that CoQ10-LIP+UTMD effectively prevented the renal morphology and function of diabetics rats from damage. The protective mechanism of CoQ10-LIP was highly associated with protecting podocyte, promoting vascular repair and inhibiting cell apoptosis. Conclusively, CoQ10-LIP in combination with UTMD might be a potential strategy to prevent occurrence of DN.

Glioma-Targeted Delivery of a Theranostic Liposome Integrated with Quantum Dots, Superparamagnetic Iron Oxide, and Cilengitide for Dual-Imaging Guiding Cancer Surgery.

Herein, a theranostic liposome (QSC-Lip) integrated with superparamagnetic iron oxide nanoparticles (SPIONs) and quantum dots (QDs) and cilengitide (CGT) into one platform is constructed to target glioma under magnetic targeting (MT) for guiding surgical resection of glioma. Transmission electron microscopy and X-ray photoelectron spectroscopy confirm the complete coencapsulation of SPIONs and QDs in liposome. Besides, CGT is also effectively encapsulated into the liposome with an encapsulation efficiency of ∼88.9%. QSC-Lip exhibits a diameter of 100 ± 1.24 nm, zeta potential of -17.10 ± 0.11 mV, and good stability in several mediums. Moreover, each cargo shows a biphasic release pattern from QSC-Lip, a rapid initial release within initial 10 h followed by a sustained release. Cellular uptake of QSC-Lip is significantly enhanced by C6 cells under MT. In vivo dual-imaging studies show that QSC-Lip not only produces an obvious negative-contrast enhancement effect on glioma by magnetic resonance imaging but also makes tumor emitting fluorescence under MT. The dual-imaging of QSC-Lip guides the accurate resection of glioma by surgery. Besides, CGT is also specifically distributed to glioma after administration of QSC-Lip under MT, resulting in an effective inhibition of tumors. The integrated liposome may be a potential carrier for theranostics of tumor.

Skin-penetrating polymeric nanoparticles incorporated in silk fibroin hydrogel for topical delivery of curcumin to improve its therapeutic effect on psoriasis mouse model.

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.

Dual Regulations of Thermosensitive Heparin-Poloxamer Hydrogel Using ε-Polylysine: Bioadhesivity and Controlled KGF Release for Enhancing Wound Healing of Endometrial Injury.

Hydrogel was not only used as an effective support matrix to prevent intrauterine adhesion after endometrial injury but also served as scaffold to sustain release of some therapeutics, especially growth factor. However, because of the rapid turnover of the endometrial mucus, the poor retention and bad absorption of therapeutic agents in damaged endometrial cavity were two important factors hindering their pharmacologic effect. Herein, a mucoadhesive hydrogel was described by using heparin-modified poloxamer (HP) as the matrix material and ε-polylysine (EPL) as functional excipient. Various EPL-HP hydrogels formulations are screened by rheological evaluation and mucoadhesion studies. It was found that the rheological and mucoadhesive properties of EPL-HP hydrogels were easily controlled by changing the amount of EPL in formulation. The storage modulus of EPL-HP hydrogel with 90 µg/mL of EPL (EPL-HP-90) was elevated to be 1.9 × 105 Pa, in accordance with the adhesion force rising to 3.18 N (10-fold higher than HP hydrogels). Moreover, in vitro release of model drug keratinocyte growth factor (KGF) from EPL-HP hydrogel was significantly accelerated by adding EPL in comparison with HP hydrogel. Both strong mucoadhesive ability and the accelerated drug release behavior for EPL-HP-90 made more of the encapsulated KGF absorbed by the uterus basal layer and endometrial glands after 8 h of administration in uterus cavity. Meanwhile, the morphology of endometrium in the injured uterus was repaired well after 3 d of treatment with KGF-EPL-HP-90 hydrogels. Compared with KGF-HP group, not only proliferation of endometrial epithelial cell and glands but also angiogenesis in the regenerated endometrium was obviously enhanced after treatment with KGF-EPL-HP-90 hydrogels. Alternatively, the cellular apoptosis in the damaged endometrium was significantly inhibited after treatment with KGF-EPL-HP-90 hydrogels. Overall, the mucoadhesive EPL-HP hydrogel with a suitable KGF release profile may be a more promising approach than HP hydrogel alone to repair the injured endometrium.

Temperature-sensitive heparin-modified poloxamer hydrogel with affinity to KGF facilitate the morphologic and functional recovery of the injured rat uterus.

Endometrial injury usually results in intrauterine adhesion (IUA), which is an important cause of infertility and recurrent miscarriage in reproductive women. There is still lack of an effective therapeutic strategy to prevent occurrence of IUA. Keratinocyte growth factor (KGF) is a potent repair factor for epithelial tissues. Here, a temperature-sensitive heparin-modified poloxamer (HP) hydrogel with affinity to KGF (KGF-HP) was used as a support matrix to prevent IUA and deliver KGF. The rheology of KGF-HP hydrogel was carefully characterized. The cold KGF-HP solution was rapidly transited to hydrogel with suitable storage modulus (G') and loss modulus (G″) for the applications of uterus cavity at temperature of 33 °C. In vitro release demonstrated that KGF was released from HP hydrogels in sustained release manner for a long time. In vivo bioluminescence imaging showed that KGF-HP hydrogel was able to prolong the retention of the encapsulated KGF in injured uterus of rat model. Moreover, the morphology and function of the injured uterus were significantly recovered after administration of KGF-HP hydrogel, which were evaluated by two-dimensional ultrasound imaging and receptive fertility. Not only proliferation of endometrial glandular epithelial cells and luminal epithelial cells but also angiogenesis of injured uterus were observed by Ki67 and CD31 staining after 7 d of treatment with KGF-HP hydrogel. Finally, a close relatively relationship between autophagy and proliferation of endometrial epithelial cells (EEC) and angiogenesis was firstly confirmed by detecting expression of LC3-II and P62 after KGF treatment. Overall, KGF-HP may be used as a promising candidate for IUA treatment.

Liposomes with Silk Fibroin Hydrogel Core to Stabilize bFGF and Promote the Wound Healing of Mice with Deep Second-Degree Scald.

How to maintain the stability of basic fibroblast growth factor (bFGF) in wounds with massive wound fluids is important to accelerate wound healing. Here, a novel liposome with hydrogel core of silk fibroin (SF-LIP) is successfully developed by the common liposomal template, followed by gelation of liquid SF inside vesicle under sonication. SF-LIP is capable of encapsulating bFGF (SF-bFGF-LIP) with high efficiency, having a diameter of 99.8 ± 0.5 nm and zeta potential of -9.41 ± 0.10 mV. SF-LIP effectively improves the stability of bFGF in wound fluids. After 8 h of incubation with wound fluids at 37 °C, more than 50% of free bFGF are degraded, while only 18.6% of the encapsulated bFGF in SF-LIP are destroyed. Even after 3 d of preincubation with wound fluids, the cell proliferation activity and wound healing ability of SF-bFGF-LIP are still preserved but these are severely compromised for the conventional bFGF-liposome (bFGF-LIP). In vivo experiments reveal that SF-bFGF-LIP accelerates the wound closure of mice with deep second-degree scald. Moreover, due to the protective effect and enhanced penetration ability, SF-bFGF-LIP is very helpful to induce regeneration of vascular vessel in comparison with free bFGF or bFGF-LIP. The liposome with SF hydrogel core may be a potential carrier as growth factors for wound healing.