Tumor Targeted Curcumin Delivery by Folate-Modified MPEG-PCL Self-Assembly Micelles for Colorectal Cancer Therapy.

INTRODUCTION: Curcumin (Cur) is a natural extract of Asian spice Curcumin longa, showing multi-targeting capability and low toxicity in anti-tumor activities. The low bioavailability restricts its application as a therapeutic agent. Folate (FA) receptors are highly expressed in many malignant tumors while low expressed in normal tissue. Herein, we developed a self-assembled FA modified MPEG-PCL micelle to incorporate Cur (FA/Nano-Cur) and applied it for colorectal cancer therapy. METHODS: We prepared FA/Nano-Cur micelles and identified their characteristics. The drug release behavior, pharmacokinetics and in vitro anti-tumor activities of FA/Nano-Cur were studied. Furthermore, the in vivo anti-tumor ability assessment and anti-tumor mechanisms investigation were carried out in murine colorectal cancer model. RESULTS: FA/Nano-Cur micelles had an average particle size of 30.47 nm. Elongated T1/2 and larger AUC were found in FA/Nano-Cur group than that in the Free Cur group. MTT assay and apoptotic study indicated the growth inhibitory effect and pro-apoptotic effect of FA/Nano-Cur were the most significant among all treatments. Moreover, the in vivo study demonstrated that FA/Nano-Cur micelles exhibited a much stronger effect to suppress tumor growth, promote tumor apoptosis and attenuate tumor angiogenesis than Free Cur and Nano-Cur micelles. CONCLUSION: The present study demonstrated FA/Nano-Cur micelles might be a promising therapeutic agent in colorectal cancer treatment with distinctive advantages of improved bioavailability, sustained drug release, tumor-targeted delivery and low toxicity.

Targeted MIP-3ß plasmid nanoparticles induce dendritic cell maturation and inhibit M2 macrophage polarisation to suppress cancer growth.

In recent decades, cancer immunotherapy has demonstrated considerable clinical advantages in cancer therapy. Particularly, the use of immunological gene therapy continues to grow in this field. Macrophage Inflammatory Protein 3 Beta (MIP-3ß) has emerged as a potential immunomodulator for anti-cancer treatments by enhancing the interaction among immune responses. In this study, we demonstrate an innovative targeted gene delivery system based on a self-assembly technique with 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP), Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA), and folic acid modified poly(ethylene glycol)-poly(ε-caprolactone) (FA-PEG-PCL) (FDMCA). Results showed that the expression of MIP-3ß was up-regulated in cancer cells following the transfection with FDMCA-pMIP-3ß, in comparison with cells transfected with DMCA-pMIP-3ß. The supernatants collected from cancer cells transfected with FDMCA-pMIP-3ß and DMCA-pMIP-3ß both instigate dendritic cell maturation, M1 polarisation of macrophages, activation and presentation of cytotoxicity in lymphocytes. Moreover, tumor growth and metastasis were markedly inhibited following the administration of the FDMCA-pMIP-3ß complex in both subcutaneous and pulmonary metastasis mice models, which is attributed to reduced angiogenesis, enhanced cancer cell apoptosis, and suppressed proliferation by activation of the immune system. Our study suggests that the MIP-3ß plasmid and FDMCA complex provide a new approach for the treatment of breast cancer.

Anti-Glioma Effect with Targeting Therapy Using Folate Modified Nano-Micelles Delivery Curcumin.

Targeted drug delivery systems have currently demonstrated considerable potential clinical benefits in cancer treatment. Curcumin has become a candidate anti-tumor drug for the therapy of glioblastoma multiforme (GBM) by increasing cell apoptosis and suppressing cell proliferation. In current research, we explored a novel targeted drug delivery system with a self-assembly measure by curcumin, MPEG-PLA and Fa-PEG-PLA. Compared with free curcumin and Cur/MPEG-PLA, Cur/Fa-PEG-PLA can remarkably suppress the growth of GL261 cells and promote apoptotic rate. Moreover, after the procession of tumor-bearing mice with curcumin/Fa-PEG-PLA complex, tumor growth in subcutaneous and intracranial tumor models were repressed via suppressing angiogenesis and facilitating apoptosis in vivo. The Curcumin/Fa-PEG-PLA nanoparticle may be a novel drug for the therapy of GBM.

Applying an innovative biodegradable self-assembly nanomicelles to deliver α-mangostin for improving anti-melanoma activity.

α-Mangostin (αM), a traditional natural product with promising application of treating a series of diseases, was limited use in clinical due to its hydrophobicity. Herein, MPEG-PCL nanomicelles were used to embed the αM for resolving hydrophobicity and improving the anti-melanoma effect of the αM. The anti-melanoma activity and potential mechanisms of biodegradable αM/MPEG-PCL nanomicelles were investigated. The αM/MPEG-PCL nanomicelles possessed a stronger effect on anti-melanoma compared to the free αM both in vitro and in vivo with a low cytotoxicity in non-tumor cell lines. In the research of mechanisms, the αM/MPEG-PCL nanomicelles inhibited the proliferation of melanoma cell, induced apoptosis via both apoptosis pathways of intrinsic and exogenous in vitro, as well as suppressed tumor growth and restrained angiogenesis in vivo, which implied that the αM/MPEG-PCL nanomicelles have potential application as a novel chemotherapeutic agent in melanoma therapy.

Oral Administration of Liposome-Apatinib and Locally Delivery of Docetaxel/MPEG-PCL by Fibrin Glue Synergistically Improve Therapeutic Effect in Colorectal Cancer.

Colorectal cancer is one of the most common and malignant cancer in the world wide. Recently, combination of target therapy and chemotherapy has generated new promise for colorectal cancer. Apatinib mesylate is a novel and highly selective VEGFR-2 inhibitor, presented with an outstanding activity of anti-angiogensis, which has the potential for treating various tumors. As a traditional chemotherapeutic drug, docetaxel (Taxotere) is a widely used semisynthetic taxoid in solid tumors. In this study, Liposome and Methoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) were constructed as drug delivery system for the delivery of apatinib (Lipo-Apa) and docetaxel (DOC/M), respectively. Co-administration of Lipo-Apa and DOC/M showed synergistically effects on inhibiting cell proliferation and inducing cell apoptosis of CT26 cells in vitro. Moreover, fibrin glue, as a biocompatible adherent hemostat, was used as a kind of vehicle for locally delivery of DOC/M in animal models, for achieving locally high concentration and prolonging releasing time. Combination of Lipo-Apa by gavage and locally delivery of DOC/M showed significantly improved anti-tumor activity in a subcutaneous xenograft model as well as in the abdominal metastasis model of colorectal cancer. In addition, promoted tumor apoptosis, inhibited proliferation and decreased tumor angiogenesis were presented by the co-administration. Finally, our study suggested that combination of oral administration of Lipo-Apa and locally delivery of DOC/M by fibrin glue, has the potential to be applied clinically in colorectal cancer therapy.

Enhanced uptake and improved anti-tumor efficacy of doxorubicin loaded fibrin gel with liposomal apatinib in colorectal cancer.

Colorectal cancer (CRC) exhibited high incidence rate worldwide and the advanced CRC had a poor prognosis. Thereupon, seeking efficient treatment for CRC is critical. Apatinib is a novel vascular epithelial growth factor receptor (VEGFR) inhibitor with inspiring therapeutic effect in some malignant cancers. In our study, doxorubicin was mixed in fibrin gel and apatinib was encapsulated with self-synthesized liposome. The results showed liposomal apatinib (Lipo-Apatinib) could enhance the intracellular uptake of doxorubicin in vitro. Moreover, compared with doxorubicin loaded fibrin gel (DOX-FG) alone, the combination of DOX-FG and Lipo-Apatinib significantly improved the anti-tumor effect in mice CRC subcutaneous model and abdominal metastasis model Drug combination successfully inhibited tumor angiogenesis and tumor proliferation, and also promoted tumor apoptosis. Our data suggested that combined therapy of DOX-FG and Lipo-Apatinib would be a promising treatment approach for CRC.