A Triterpene-Based bioactive drug delivery system for combined chemotherapy of liver cancer.

Carrier materials always account for the majority particularly in nanosized formulations, which are administrated along with the active ingredient part might result in metabolism related toxicity. The usage of bioactive excipients could not only reduce the sided effect but also provide additional therapeutic effects. In the present study, a triterpene based micellar drug delivery system was developed using a bioactive solanesol derivative. Solanesylamine was prepared firstly followed by conjugating with poly (ethylene glycol) using maleic acid amide linkage. The amphiphilic drug carrier PEGylated (2-propyl-3-methylmaleic acid)-block-solanesol amine (mPEG-CDM-NH-SOL) could be formed into micelles and loaded with doxorubicin (DOX) inside. The micelles were about 112 nm in size and the drug loading content was about 5.97 wt%. An acid triggered drug release behavior was obviously observed for the DOX loaded pH-sensitive micelle mPEG-CDM-NH-SOL-DOX. While not for DOX-loaded micelles without pH-sensitivity (mPEG-NHS-NH-SOL). CCK8 assay showed that the micelles of PEGylated solanesylamines exhibited certain inhibitory effect on tumor cells at high concentration and the pH sensitive ones seemed more toxic. In vivo studies showed that the pH sensitive mPEG-CDM-NH-SOL-DOX had a superior anti-tumor effect, indicating its great potential in cancer treatment.

Dopamine-modified poly(ε-caprolactone) micelles for pH controlled delivery of bortezomib.

Poly(ethylene glycol)-poly(ε-caprolactone) (PEG-b-PCL) micelles have been widely used as drug delivery vehicles for cancer therapies. Because of the lack of functional groups, the use of PEG-b-PCL in drug delivery system is greatly limited and structural modifications is needed. In this work, chemical modification at the terminus of PEG-b-PCL was performed via the "grafting from" polymerization method. A poly(dopamine methyl acrylamide) segment was introduced containing multiple catechol groups, which could attach bortezomib (BTZ) to the chain of the polymer through the formation of a pH-sensitive borate bond. This method greatly enhanced the loading capacity of BTZ into the micelles. Additionally, the controlled release of BTZ in response to the acidic environment of a tumor was realized. High loading capacity, stimuli-responsiveness, biodegradability, and compatibility were integrated in the PEG-b-PCL-based system. In vitro and in vivo studies demonstrated that superior tumor inhibition without obvious side effects can be achieved by the BTZ-loaded PEG-b-PCL-b-PDMA micelles.

Bicomponent polymeric micelles for pH-controlled delivery of doxorubicin.

Stimuli-responsive drug delivery systems (DDSs) are expected to realize site-specific drug release and kill cancer cells selectively. In this study, a pH-responsive micelle was designed utilizing the pH-sensitivity of borate bonds formed between dopamine and boronic acid. First, methyl (polyethylene glycol)-block-polycaprolactone (mPEG-PCL) was conjugated with 4-cyano-4-(thiobenzoylthio)pentanoic acid (CTP) to obtain a macroinitiator. Two different segments poly(dopamine methacrylamide) (PDMA) and poly(vinylphenylboronic acid) (PVBA) were then grafted to the end of mPEG-PCL. Two triblock copolymers, mPEG-PCL-PDMA and mPEG-PCL-PVBA, were then obtained by reversible addition-fragmentation transfer (RAFT) polymerization. These copolymers and their mixture self-assembled in aqueous solution to form micelles that were able to load hydrophobic anticancer drug doxorubicin (DOX). These two-component micelles were found to be pH-sensitive, in contrast to the one-component micelles. Furthermore, MTT studies showed that the micelles were almost nontoxic. The DOX-loaded micelles showed cytotoxicity equivalent to that of DOX at high concentration. In vivo antitumor experiments showed that this pH-sensitive polymeric micellar system had an enhanced therapeutic effect on tumors. These two-component boronate-based pH micelles are universally applicable to the delivery of anticancer drugs, showing great potential for cancer therapy.

Hydrazone-Containing Triblock Copolymeric Micelles for pH-Controlled Drug Delivery.

In this study, the structure-activity relationship of amphiphilic block copolymer micelles as nanosized drug delivery system was revealed. Firstly, a biodegradable triblock polymers PEG-DiHyd-PLA containing hydrazone bond was synthesized through the ring-opening polymerization. In this method, PEG-DiHyd-Phenol was used as the initiator and L-lactide as the monomer. Then, the polymeric micelles were formed and used as nano-drug carriers with pH sensitivity. The structure and composition of the polymer were characterized by infrared (IR), nuclear magnetic resonance (1H-NMR), and gel permeation chromatography (GPC), we characterized the self-assembling process of the triblock polymers and the pH sensitivity of the micelles by the means of transmission electron microscopy (TEM), dynamic light scattering method (DLS). Doxorubicin (DOX) acts as the model drug, and we researched the capacities of drug loading and release in vitro of the micelles. MTT experiments showed that the blank micelles of PEG-DiHyd-PLA were not cytotoxic to tumor cells (HepG-2, MCF-7) and normal cell (L-02 cells), but the DOX loaded ones displayed more toxicity than the ones without hydrazone, which was consistent to the further confocal laser scanning microscopy and flow cytometry study.