Lu Sun

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.

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.

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.

Polymeric nanoassemblies entrapping curcumin overcome multidrug resistance in ovarian cancer.

The increasing emergence of multidrug-resistant (MDR) cells presents a challenge to effective cancer therapy. Curcumin (CUR) has multifunctional anticancer properties, but its clinical use has been limited by poor solubility. We developed biodegradable polymeric micelles entrapping CUR in order to improve its antitumor activity and to explore whether it could treat MDR cells. This delivery system produced small micelles with a high encapsulation efficiency, good stability, and slow release of CUR. CUR micelles showed cytotoxic effects in wild-type drug-sensitive A2780s and in paclitaxel-resistant A2780t ovarian adenocarcinoma cells. The concentration of free CUR that reduced cell viability by 50% (IC50) was 1.5 fold and 1.2 fold higher than that of CUR micelles in A2780s and A2780t cells, respectively. Cellular uptake studies indicated that delivery by micelles improved CUR uptake into both cell lines. Cell cycle analysis suggested that CUR micelles induced apoptosis and enhanced G2/M arrest. Overall, CUR micelles may provide a novel strategy to improve the clinical management of MDR ovarian cancer.

In Vitro and In Vivo Safety Evaluation of Biodegradable Self-Assembled Monomethyl Poly (Ethylene Glycol)–Poly(ε-Caprolactone)–Poly (Trimethylene Carbonate) Micelles

Safety evaluation of self-assembled polymeric micelles is important for biomedical involvement in drug delivery systems in the future. In this study, biodegradable monomethyl poly (ethylene glycol)-poly (ε-caprolactone)-poly (trimethylene carbonate) [MPEG-P(CL-co-TMC)] copolymer was synthesized and characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance analysis, and gel permeation chromatography. MPEG-P(CL-co-TMC) micelles were prepared by self-assembly without any organic solvent. The present study was conducted to assess the safety of blank MPEG-P(CL-co-TMC) micelles both in vitro and in vivo. Particle size (30.09 ± 0.06 nm) and zeta potential (0.067 ± 0.027 mV) of obtained micelles were determined by Malvern laser particle size analyzer. The results of in vitro toxicity evaluation implied that the prepared micelles did not cause hemolysis or severely cell toxicity. Meanwhile, we did not observe any toxic response or histopathological changes in the study of in vivo acute toxicity evaluation and histopathological study of MPEG-P(CL-co-TMC) micelles. In conclusion, the maximal tolerance dose of MPEG-P(CL-co-TMC) micelles (100 mg/mL) by intravenous injection was supposed to be greater than 10 g/kg body weight. Therefore, it might have potential applications in biomedical field.

Prevention of desiccation induced postsurgical adhesion by thermosensitive micelles.

Tissue desiccation is a common cause of postsurgical peritoneal adhesion, which leads a variety of adverse consequences in clinic. Until now, many approaches have been advocated to prevent postsurgical adhesions, but the therapeutic effects were not very encouraging. In this work, biodegradable and thermosensitive poly(ɛ-caprolactone)-poly(ethylene glycol)-poly(ɛ-caprolactone) (PCL-PEG-PCL) micelles were prepared and assigned for anti-adhesion studies. The micelles were a free flowing sol at low temperature, but instantly inverted into a non-flowing gel at physiological temperature, which could serve as a potential candidate as anti-adhesion barrier. A novel cecum desiccation rat model was established and used for anti-adhesion studies. The micelles were sol state before use, which could cover the injured cecum unrestrictedly, and then formed gel in body temperature and adhered to the injured sites. All the rats in the control group developed adhesions with score 5 or 4, whereas none in the micelle-treated group developed adhesions with score 5 or 4 (P<0.001, Mann-Whitney U test). Histopathological assessment also confirmed that the micelles exhibited excellent anti-adhesion effects on desiccation-induced peritoneal adhesion. Adhesiveness and degradation behavior of the micelles suggested that the micelles could adhere to the injured cecum and prevent adhesion in the critical time of healing process. The results indicated that the thermosensitive micelles could serve as an effective anti-adhesion barrier.