Guang Hui Gao

Stimulus‐Sensitive Polymeric Nanoparticles and Their Applications as Drug and Gene Carriers

Polymeric nanoparticles are promising candidates as drug and gene carriers. Among polymeric nanoparticles, those that are responsive to internal or external stimuli are of greater interest because they allow more efficient delivery of therapeutics to pathological regions. Stimulus-sensitive polymeric nanoparticles have been fabricated based on numerous nanostructures, including micelles, vesicles, crosslinked nanoparticles, and hybrid nanoparticles. The changes in chemical or physical properties of polymeric nanoparticles that occur in response to single, dual, or multiple stimuli endow these nanoparticles with the ability to retain cargoes during circulation, target the pathological region, and release their cargoes after cell internalization. This Review focuses on the most recent developments in the preparation of stimulus-sensitive polymeric nanoparticles and their applications in drug and gene delivery.

Environmental pH-sensitive polymeric micelles for cancer diagnosis and targeted therapy.

The delivery and control over the release of hydrophobic imaging markers for cancer diagnosis or pharmaceutical agents for targeted therapy are of considerable interest. Nano-sized pH-sensitive polymeric micelles that rely on the enhanced permeability and retention (EPR) of vasculature and the low-pH microenvironment in cancer tissue are emerging as stimuli-responsive targeted therapies that can simultaneously release diagnostic and therapeutic agents into a cancerous region. This review focuses on the developments of pH-sensitive polymeric micelles and their biomedical applications in cancer diagnosis and targeted therapy.

pH-responsive polymeric micelle based on PEG-poly(β-amino ester)/(amido amine) as intelligent vehicle for magnetic resonance imaging in detection of cerebral ischemic area.

A series of pH-responsive polymeric micelles is developed to act as intelligent carriers to deliver iron oxide (Fe(3)O(4)) nanoparticles and respond rapidly to an acidic stimuli environment for magnetic resonance imaging (MRI). The polymeric micelle can be self-assembled at physiological pH by a block copolymer, consisting of a hydrophilic methoxy poly(ethylene glycol) (PEG) and a pH-responsive poly(β-amino ester)/(amido amine) block. Consequently, the Fe(3)O(4) nanoparticles can be well encapsulated into polymeric micelles due to the hydrophobic interaction, shielded by a PEG coronal shell. In an acidic environment, however, the pH-responsive component, which has ionizable tert-amino groups on its backbone, can become protonated to be soluble and release the hydrophobic Fe(3)O(4) nanoparticles. The Fe(3)O(4)-loaded polymeric micelle was measured by dynamic light scattering (DLS), superconducting quantum interference device (SQUID) and a 3.0T MRI scanner. To assess the ability of this MRI probe as a pH-triggered agent, we utilize a disease rat model of cerebral ischemia that produces acidic tissue due to its pathologic condition. We found gradual accumulation of Fe(3)O(4) nanoparticles in the brain ischemic area, indicating that the pH-triggered MRI probe may be effective for targeting the acidic environment and diagnostic imaging of pathologic tissue.

The use of pH-sensitive positively charged polymeric micelles for protein delivery

In this investigation, a nano-sized protein-encapsulated polymeric micelle was prepared by self-assembling human serum albumin (HSA) as a model protein and degradable block copolymer methoxy poly(ethylene glycol)-poly(β-amino ester) (PEG-PAE) with piperidine and imidazole rings. From the zeta potential measurement, the protein-encapsulated polymeric micelle showed a pH-tuning charge conversion from neutral to positive when pH decreases from 7.8 to 6.2. It was envisioned that the pH-tunable positively charged polymeric micelle could enhance the protein delivery efficiency and, simultaneously, target to the pH-stimuli tissue, such as cancerous tissue or ischemia. The pH-dependent particle size and scattering intensity were also measured and showed 50-70 nm particle size. Consequently, the circular dichroism (CD) spectroscopy confirmed that the secondary structure of albumin was unaffected during the pH changing process. The in vitro cytotoxicity for the polymeric micelle was evaluated on MDA-MB-435 cell lines and no obvious toxicity could be observed when the polymer concentration was below 200 μg/mL. To assess the ability of this pH-tunable positively charged polymeric micelle as a vehicle for protein delivery to in vivo acidic tissues, we utilized a disease rat model of cerebral ischemia that produced an acidic tissue due to its pathologic condition. The rat was intravenously injected with the Cy5.5-labled albumin-encapsulated polymeric micelle. We found a gradual increase in fluorescence signals of the brain ischemic area, indicating that the pH-tuning positively charged protein-encapsulated polymeric micelle could be effective for targeting the acidic environment and diagnostic imaging.

Biodegradable oligo(amidoamine/β-amino ester) hydrogels for controlled insulin delivery

An injectable biodegradable hydrogel system based on oligo(amidoamine/β-amino ester) (OAAAE) was designed and synthesized for controlled release of insulin under the physiological conditions. OAAAE was prepared in one step via the Michael-addition oligomerization of the secondary amine groups of 4,4-trimethylene dipiperidine (TMDP) with the vinyl groups of 1,8-octylene diacrylamide (ODA) and 1,6-hexane diol diacrylate (HDA). The formed oligomer was characterized by 1H NMR and gel permeation chromatography (GPC). OAAAE in aqueous solution (20 wt%) underwent a gel–sol transition in the pH range of 6.8–7.4. A complex hydrogel was formed when mixing insulin with the oligomer solution followed by increasing pH and temperature. Degradation of the hydrogel, influence of insulin on gel phase and gel strength, in vitro cytotoxicity of OAAAE, in vitro and in vivo release of insulin from the complex hydrogel were investigated. Furthermore, the in vivo release profile of insulin from the complex hydrogel was compared with that from the neutral hydrogel.

Highly cited research articles in Journal of Controlled Release: Commentaries and perspectives by authors

Abstract To celebrate the success of the Journal of Controlled Release and the research covered in the journal, here we highlight some of the most cited research articles in the history of the journal. Based on the literature search in Google Scholar in July 2013, we identified ~30 research articles that have received most number of citations. Authors of these articles were invited to provide a commentary on these articles. This compilation of commentaries gives a historical perspective and current status of research covered in these articles.

Construction of redox/pH dual stimuli-responsive PEGylated polymeric micelles for intracellular doxorubicin delivery in liver cancer

A new type of redox and pH dual-responsive biodegradable polypeptide micelle was developed based on the disulfide-linked methoxy poly(ethylene glycol)-b-poly[2-(dibutylamino)ethylamine-L-glutamate] (mPEG-SS-PNLG) copolymer and applied as an efficient and intelligent carrier to rapidly trigger the intracellular release of doxorubicin (DOX). The mPEG-SS-PNLG was synthesized by a combination of ring-opening polymerization using mPEG-cystamine as a macroinitiator and a side-chain aminolysis reaction. The cumulative release profile of the DOX-loaded mPEG-SS-PNLG (DOX-mPEG-SS-PNLG) micelles indicated a low level of drug release (approximately 25 wt% within 24 h) at pH 7.4, which was significantly accelerated at a lower pH of 5.0 and a higher reducing environment (over 95 wt% in 24 h), demonstrating unambiguous redox/pH dual-responsive controlled drug release capability. An in vitro cytotoxicity test indicated that empty mPEG-SS-PNLG micelles were nontoxic to HepG2 cells up to a tested concentration of 200 μg mL−1. Confocal laser scanning microscopy observations revealed that DOX-loaded mPEG-SS-PNLG micelles efficiently released DOX into human hepatocellular carcinoma HepG2 cells following 24 h of incubation. Importantly, the DOX-loaded mPEG-SS-PNLG micelles significantly increased in vivo therapeutic efficacy toward HepG2 cells in comparison with the free-DOX and control groups. The successful demonstrations indicate that redox and pH dual-responsive mPEG-SS-PNLG micelles are promising candidates for delivering anti-cancer drugs.

A Biodegradable Polymersome with pH-Tuning On-Off Membrane Based on Poly(β-amino ester) for Drug Delivery

A nanoscale biodegradable polymersome with pH-tuning on-off membrane is prepared via the self-assembly of poly(β-amino ester)-based amphiphilic copolymers. The pH-sensitive polymersome-like vesicle structure includes two layers that can encapsulate either hydrophobic or hydrophilic therapeutic drugs at physiological pH 7.4. Below a pH of 7.0, the polymersome membrane forms tunnels through which the drug cargo can be rapidly released. The size and morphology of the polymersome are measured by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The pH sensitivity is confirmed by fluorescence spectroscopy. The pH-sensitive drug-delivery polymersome provides a simple and powerful smart carrier for the delivery and controlled release of drugs.

Evaluation of pH‐Sensitive Poly(β‐amino ester)‐graft‐poly(ethylene glycol) and its Usefulness as a pH‐Sensor and Protein Carrier

In this study, some possible biomedical applications of a pH-sensitive and amphiphilic copolymer as a pH sensor and protein delivery system are reported. PAE-g-PEG was used as a pH-sensitive polymer that can exhibit a sharp pH-dependent transition. Various fluorescent dyes including pyrene and RITC can be used to label the pH-sensitive polymer PAE-g-PEG, which was evaluated for protein encapsulation. pH-sensing was possible by observing excimer formation of the labeled pyrene via pH-dependent expansion of the polymeric chain. Also, it was confirmed that FITC-BSA could be entrapped in RITC-labeled pH-sensitive micelles of PAE-g-PEG by FRET. As a result, PAE-g-PEG can be a pH sensor and carrier for protein delivery.