Qinjie Wu

A biodegradable hydrogel system containing curcumin encapsulated in micelles for cutaneous wound healing.

A biodegradable in situ gel-forming controlled drug delivery system composed of curcumin loaded micelles and thermosensitive hydrogel was prepared and applied for cutaneous wound repair. Curcumin is believed to be a potent antioxidant and anti-inflammatory agent. Due to its high hydrophobicity, curcumin was encapsulated in polymeric micelles (Cur-M) with high drug loading and encapsulation efficiency. Cur-M loaded thermosensitive hydrogel (Cur-M-H) was prepared and applied as wound dressing to enhance the cutaneous wound healing. Cur-M-H was a free-flowing sol at ambient temperature and instantly converted into a non-flowing gel at body temperature. In vitro studies suggested that Cur-M-H exhibited well tissue adhesiveness and could release curcumin in an extended period. Furthermore, linear incision and full-thickness excision wound models were employed to evaluate the in vivo wound healing activity of Cur-M-H. In incision model, Cur-M-H-treated group showed higher tensile strength and thicker epidermis. In excision model, Cur-M-H group exhibited enhancement of wound closure. Besides, in both models, Cur-M-H-treated groups showed higher collagen content, better granulation, higher wound maturity, dramatic decrease in superoxide dismutase, and slight increase in catalase. Histopathologic examination also implied that Cur-M-H could enhance cutaneous wound repair. In conclusion, biodegradable Cur-M-H composite might have great application for wound healing.

Improving antiangiogenesis and anti-tumor activity of curcumin by biodegradable polymeric micelles.

For developing aqueous formulation and improving anti-tumor activity of curcumin (Cur), we prepared Cur encapsulated MPEG-PCL micelles by solid dispersion method without using any surfactants or toxic organic solvent. Cur micelles could be lyophilized into powder form without any cryoprotector or excipient, and the re-dissolved Cur micelles are homogenous and stable. Molecular modeling study suggested that Cur tended to interact with PCL serving as a core embraced by PEG as a shell. After Cur was encapsulated into polymeric micelles, cytotoxicity and cellular uptake were both increased. Cur micelles had a stronger inhibitory effect on proliferation, migration, invasion, and tube formation of HUVECs than free Cur. Besides, Cur micelles showed a sustained in vitro release behavior and slow extravasation from blood vessels in transgenic zebrafish model. Embryonic angiogenesis and tumor-induced angiogenesis were both dramatically inhibited by Cur micelles in transgenic zebrafish model. Furthermore, Cur micelles were more effective in inhibiting tumor growth and prolonged survival in both subcutaneous and pulmonary metastatic LL/2 tumor models. In pharmacokinetic and tissue distribution studies, Cur micelles showed higher concentration and longer retention time in plasma and tumors. Our findings suggested that Cur micelles may have promising applications in pulmonary carcinoma therapy.

Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous pulmonary metastasis

This work aims to develop curcumin (Cur) loaded biodegradable self-assembled polymeric micelles (Cur-M) to overcome poor water solubility of Cur and to meet the requirement of intravenous administration. Cur-M were prepared by solid dispersion method, which was simple and easy to scale up. Cur-M had a small particle size of 28.2 ± 1.8 nm and polydisperse index (PDI) of 0.136 ± 0.050, and drug loading and encapsulation efficiency of Cur-M were 14.84 ± 0.11% and 98.91 ± 0.70%, respectively. Besides, in vitro release profile showed a significant difference between rapid release of free Cur and much slower and sustained release of Cur-M. Cytotoxicity study showed that the encapsulated Cur remained its potent anti-tumor effect. Furthermore, Cur-M were more effective in inhibiting tumor growth and spontaneous pulmonary metastasis in subcutaneous 4T1 breast tumor model, and prolonged survival of tumor-bearing mice. In addition, immunofluorescent and immunohistochemical studies also showed that tumors of Cur-M-treated mice had more apoptosis cells, fewer microvessels, and fewer proliferation-positive cells. In conclusion, polymeric micelles encapsulating Cur were developed with enhanced anti-tumor and anti-metastasis activity on breast tumor, and Cur-M is excellent water-based formulation of Cur which may serve as a candidate for breast cancer therapy.

Curcumin-encapsulated polymeric micelles suppress the development of colon cancer in vitro and in vivo.

To develop injectable formulation and improve the stability of curcumin (Cur), Cur was encapsulated into monomethyl poly (ethylene glycol)-poly (ε-caprolactone)-poly (trimethylene carbonate) (MPEG-P(CL-co-TMC)) micelles through a single-step solid dispersion method. The obtained Cur micelles had a small particle size of 27.6 ± 0.7 nm with polydisperse index (PDI) of 0.11 ± 0.05, drug loading of 14.07 ± 0.94%, and encapsulation efficiency of 96.08 ± 3.23%. Both free Cur and Cur micelles efficiently suppressed growth of CT26 colon carcinoma cells in vitro. The results of in vitro anticancer studies confirmed that apoptosis induction and cellular uptake on CT26 cells had completely increased in Cur micelles compared with free Cur. Besides, Cur micelles were more effective in suppressing the tumor growth of subcutaneous CT26 colon in vivo, and the mechanisms included the inhibition of tumor proliferation and angiogenesis and increased apoptosis of tumor cells. Furthermore, few side effects were found in Cur micelles. Overall, our findings suggested that Cur micelles could be a stabilized aqueous formulation for intravenous application with improved antitumor activity, which may be a potential treatment strategy for colon cancer in the future.

5-FU-hydrogel inhibits colorectal peritoneal carcinomatosis and tumor growth in mice

BackgroundColorectal peritoneal carcinomatosis (CRPC) is a common form of systemic metastasis of intra-abdominal cancers. Intraperitoneal chemotherapy is a preferable option for colorectal cancer. Here we reported that a new system, 5-FU-loaded hydrogel system, can improve the therapeutic effects of intraperitoneal chemotherapy.MethodsA biodegradable PEG-PCL-PEG (PECE) triblock copolymer was successfully synthesized. The biodegradable and temperature sensitive hydrogel was developed to load 5-FU. Methylene blue-loaded hydrogel were also developed for visible observation of the drug release. The effects and toxicity of the 5-FU-hydrogel system were evaluated in a murine CRPC model.ResultsThe hydrogel system is an injectable flowing solution at ambient temperature and forms a non-flowing gel depot at physiological temperature. 5-FU-hydrogel was subsequently injected into abdominal cavity in mice with CT26 cancer cells peritoneal dissemination. The results showed that the hydrogel delivery system prolonged the release of methylene blue; the 5-FU-hydrogel significantly inhibited the peritoneal dissemination and growth of CT26 cells. Furthermore, intraperitoneal administration of the 5-FU-hydrogel was well tolerated and showed less hematologic toxicity.ConclusionsOur data indicate that the 5-FU-hydrogel system can be considered as a new strategy for peritoneal carcinomatosis, and the hydrogel may provide a potential delivery system to load different chemotherapeutic drugs for peritoneal carcinomatosis of cancers.

Strategies of polymeric nanoparticles for enhanced internalization in cancer therapy

In order to achieve long circulation time and high drug accumulation in the tumor sites via the EPR effects, anticancer drugs have to be protected by non-fouling polymers such as poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), dextran, and poly(acrylic acid) (PAA). However, the dense layer of stealth polymer also prohibits efficient uptake of anticancer drugs by target cancer cells. For cancer therapy, it is often more desirable to accomplish rapid cellular uptake after anticancer drugs arriving at the pathological site, which could on one hand maximize the therapeutic efficacy and on the other hand reduce probability of drug resistance in cells. In this review, special attention will be focused on the recent potential strategies that can enable drug-loaded polymeric nanoparticles to rapidly recognize cancer cells, leading to enhanced internalization.

A Powerful CD8+ T‐Cell Stimulating D‐Tetra‐Peptide Hydrogel as a Very Promising Vaccine Adjuvant

A novel vaccine adjuvant based on a supramolecular hydrogel of a D-tetra-peptide is reported. Antigens can be easily incorporated into the hydrogel by a vortex or by gently shaking before injection. The vaccines can stimulate strong CD8+ T-cell responses, which significantly inhibits tumor growth. This novel adjuvant is expected to enable a wide range of sub-unit vaccines and help the production of antibodies.

Improving intraperitoneal chemotherapeutic effect and preventing postsurgical adhesions simultaneously with biodegradable micelles

The two major concerns after cytoreductive surgery of abdominal and pelvic malignancies are residual tumors and peritoneal adhesions, which are inevitable and have great impact on prognosis. Therefore, to improve the intraperitoneal chemotherapeutic effect and prevent postsurgical adhesions simultaneously after surgery, we developed a novel strategy that combines the controlled drug delivery system (CDDS) with an antiadhesion barrier. Biodegradable poly(ethylene glycol)-poly(ɛ-caprolactone)-poly(ethylene glycol) (PECE) copolymer formed micelles in water, which turned instantly into a nonflowing gel at body temperature as a result of micellar aggregation. Effectiveness of doxorubicin-loaded PECE micelles (Dox-M) in improving intraperitoneal chemotherapeutic effect and preventing adhesions was investigated. Subsequently, we established a novel mouse model for postsurgical residual tumors and peritoneal adhesions, in which Dox-M could improve intraperitoneal chemotherapeutic effect and prevent postsurgical peritoneal adhesions simultaneously. Thus, it is a promising strategy to combine the CDDS and barrier method to improve the intraperitoneal chemotherapeutic effect and prevent peritoneal adhesions simultaneously after surgery.

AAV-mediated gene transfer of human pigment epithelium-derived factor inhibits Lewis lung carcinoma growth in mice.

Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, and mechanisms through which PEDF exerts its antitumour activity have recently been defined. The aim of our research was to evaluate the ability of adeno-associated virus (AAV) vector-mediated transfer of human PEDF to inhibit Lewis lung carcinoma (LCC) cell growth. Intratumoural injection of AAV-PEDF caused significant reduction of the tumour volume and prolonged the survival time of mice bearing LLC cells, which were associated with decreased microvessel density and increased apoptosis in the tumours. AAV vectors represent a very promising tool for cancer gene therapy. No noticeable toxicity concerning AAV was detected as inferred from monitoring changes in animal body weight as well as basic organ structure and histological morphology, and by analyzing mouse liver and kidney function. Our findings indicate that AAV-mediated PEDF gene expression may offer an active approach to inhibit LLC growth and that treatment with AAV-PEDF may provide a promising therapeutic strategy in lung cancer treatment.

Co-delivery of doxorubicin and curcumin by polymeric micelles for improving antitumor efficacy on breast carcinoma

To date, combination chemotherapy has become a standard regimen to treat cancer patients. However, combination therapy with drugs having distinct properties such as solubility generally requires use of multiple carriers or solvents, which limits the likelihood of simultaneous delivery. In this work, we used biodegradable poly(ethylene glycol)–poly(e-caprolactone) (mPEG–PCL) micelles as the co-delivery system to load hydrophilic doxorubicin (Dox) and hydrophobic curcumin (Cur) to achieve combination therapy. The co-encapsulation of Dox and Cur into mPEG–PCL micelles was carried out by a simple self-assembly procedure, which was absent of organic solvents, surfactants and vigorous stirring. The prepared Dox and Cur co-loaded micelles (Dox–Cur-M) were monodisperse with small particle size, high encapsulation efficiency (EE) and sustained release behavior. Furthermore, we found the Dox–Cur-M exhibited remarkable progress in either cytotoxic activities or apoptotic effects compared with Dox-M or Cur-M at equivalent concentrations, which was primarily attributed to enhanced cellular uptake of Dox by Cur. In addition, in a subcutaneous 4T1 breast tumor model in vivo, the Dox–Cur-M was more effective in suppressing tumor growth and spontaneous pulmonary metastasis in comparison with the same dose of Dox-M and Cur-M. In conclusion, micellar co-delivery of Dox and Cur could synergistically potentiate antitumor effects on breast tumor.