Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel.

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

An EGCG-mediated self-assembled micellar complex acts as a bioactive drug carrier.

Epigallocatechin gallate (EGCG) has attracted the increasing attention of many researchers, especially in the field of tumor therapy. However, EGCG has poor fat solubility, low stability, low bioavailability, and a high effective dose in vivo. Traditional drug delivery methods are difficult to deliver the water-soluble EGCG efficiently and in high doses to tumor sites. To address these issues, a new type of strategy has been tried in this study to transform EGCG from a "Bioactive natural ingredient" into a "Bioactive drug carrier". Briefly, the EGCG was modified with a fat-soluble 9-fluorene methoxy carbonyl (Fmoc) motif, and the obtained EGCG-Fmoc showed a considerable improvement in lipid solubility and stability. Interestingly, EGCG-Fmoc obtained the characteristic of self-assembly in water, making it easier to take up by tumor cells. Furthermore, the self-assembled nanocomplex exhibited paclitaxel encapsulation performance and could achieve the dual delivery of EGCG and paclitaxel.

Combined Biomimetic MOF-RVG15 Nanoformulation Efficient Over BBB for Effective Anti-Glioblastoma in Mice Model.

Introduction: The blood-brain barrier (BBB) is a key obstacle to the delivery of drugs into the brain. Therefore, it is essential to develop an advanced drug delivery nanoplatform to solve this problem. We previously screened a small rabies virus glycoprotein 15 (RVG15) peptide with 15 amino acids and observed that most of the RVG15-modified nanoparticles entered the brain within 1 h of administration. The high BBB penetrability gives RVG15 great potential for brain-targeted drug delivery systems. Moreover, a multifunctional integrated nanoplatform with a high drug-loading capacity, tunable functionality, and controlled drug release is crucial for tumor treatment. Zeolitic imidazolate framework (ZIF-8) is a promising nanodrug delivery system. Methods: Inspired by the biomimetic concept, we designed RVG15-coated biomimetic ZIF-8 nanoparticles (RVG15-PEG@DTX@ZIF-8) for docetaxel (DTX) delivery to achieve efficient glioblastoma elimination in mice. This bionic nanotherapeutic system was prepared by one-pot encapsulation, followed by coating with RVG15-PEG conjugates. The size, morphology, stability, drug-loading capacity, and release of RVG15-PEG@DTX@ZIF-8 were thoroughly investigated. Additionally, we performed in vitro evaluation, cell uptake capacity, BBB penetration, and anti-migratory ability. We also conducted an in vivo evaluation of the biodistribution and anti-glioma efficacy of this bionic nanotherapeutic system in a mouse mode. Results: In vitro studies showed that, this bionic nanotherapeutic system exhibited excellent targeting efficiency and safety in HBMECs and C6 cells and high efficiency in crossing the BBB. Furthermore, the nanoparticles cause rapid DTX accumulation in the brain, allowing deeper penetration into glioma tumors. In vivo antitumor assay results indicated that RVG15-PEG@DTX@ZIF-8 significantly inhibited glioma growth and metastasis, thereby improving the survival of tumor-bearing mice. Conclusion: Our study demonstrates that our bionic nanotherapeutic system using RVG15 peptides is a promising and powerful tool for crossing the BBB and treating glioblastoma.

Efficient antiglioblastoma therapy in mice through doxorubicin-loaded nanomicelles modified using a novel brain-targeted RVG-15 peptide.

Glioblastoma (GBM) is an aggressive malignancy and therapeutic options are limited due to the presence of the blood-brain barrier (BBB). RVG-29, a 29-amino-acid polypeptide derived from the rabies virus glycoprotein (RVG), has excellent brain-targeted capacity across the BBB. We reduced the size of this peptide to get a15-amino-acid polypeptide (RVG-15), while retaining its brain-targeted capacity across the BBB. First, we synthesized a novel nanocarrier RVG-15-PEG2000-DSPE. Next, DOX-loaded polymeric micelles (DOX RVG-15-PMs) were prepared in an electrostatic interaction-dependent manner. Finally, we evaluated its antitumor benefits in vitro at the cellular level and in vivo using an in situ tumour-bearing mouse model. MALDI-TOF-MS and FTIR spectra confirmed the successful synthesis of the novel nanocarrier. The prepared DOX RVG-15-PMs displayed even size distribution, a high entrapment efficiency and satisfactory in vitro release behaviour. In vitro blank RVG-15-PMs were excellent, safe and highly biocompatible as drug delivery carriers. DOX-loaded micelles were easily taken up by C6 cells and could effectively inhibit cancer development and metastasis. In vivo, DOX RVG-15-PMs delayed weight loss, prevented cancer cell metastasis and accelerated cancer cell apoptosis in tumour-bearing mice. Our novel brain-targeted nanocarrier is highly feasible, while DOX RVG-15-PMs exert significant antiglioma effects, both in vitro and in vivo.

Improved Antitumor Outcomes for Colon Cancer Using Nanomicelles Loaded with the Novel Antitumor Agent LA67.

BACKGROUND: LA67 is a derivative of triptolide that exhibits strong antitumor activity. This derivative has a better safety profile than triptolide, but is limited by poor aqueous solubility. AIM AND METHODS: To improve solubility and further increase therapeutic efficacy, we prepared LA67-loaded polymeric micelles (LA67-PMs) using a film hydration method. The physicochemical properties of LA67-PMs were investigated, and the antitumor activity of this formulation against Colon26 (C26) cancer cell line was evaluated in vitro and in vivo with LA67 as a control. RESULTS: Polymeric micelles containing LA67 had a particle size of 17.88 nm and a drug entrapment efficiency of 94.84%. This formulation dispersed completely in aqueous solution and exhibited slow, sustained release of LA67. Cellular uptake assay showed that LA67-PMs delivered LA67 to cancer cells with greater efficiency than free LA67, which resulted in increased LA67 accumulation in cancer cells. Cell counting kit 8 (CCK-8) assay showed that blank polymeric micelles (PMs) exhibited low toxicity and LA67-PMs exerted pronounced anti-proliferation effects against C26 cells. Furthermore, LA67-PMs induced apoptosis and repressed migration more effectively than free LA67. In vivo evaluation of antitumor activity showed that LA67-PMs inhibited tumor growth and distant organ metastasis to a greater extent than LA67, which resulted in improved survival rate. The potential mechanisms of these effects may have been induction of apoptosis, inhibition of cell proliferation, and neovascularization. CONCLUSION: Our study showed that LA67-PMs may be a promising formulation for treatment of colon cancer.