Ngoc Ha Hoang

Triblock copolymers for nano-sized drug delivery systems

Abstract Triblock copolymers have been widely used as a material for developing drug delivery systems (DDS). In terms of architecture, triblock copolymers could be classified into symmetric and asymmetric triblock copolymers. Different types of nano-sized structures such as star micelles, flower-like micelles, and polymer vesicles could be prepared from these block copolymers, which would be very potential in delivering various types of agents such as chemical drugs, genes, and contrast agents. Additionally, the nano-sized carriers have been fabricated for environmentally sensitive (pH-sensitive or temperature sensitive) DDS or for enhancing the gene delivery efficiency. Due to their versatility in structures and drug delivery capacity, the application of triblock copolymers would definitely be expanded in near future.

Nanomedicines for oral administration based on diverse nanoplatform

Nanotechnology has been applied to the oral drug delivery for enhancing bioavailability after oral administration. Numerous forms of reported nanomedicines are classified as lipid based nanomedicine (LBNM), polymer based nanomedicine (PBNM), and nanosuspension. LBNM includes self nano-emulsifying drug delivery systems, liposomes and solid lipid nanoparticle (SLN). PBNM includes polymeric nanoparticles and polymeric micelles. Unlike intravenous administration, oral administration has more complicated barriers that are hard to overcome. The various nanoplatforms described above are used to surmount physical and bio-chemical barriers due to advantageous characteristics of nanoplatforms. The characteristics of nanoplatforms including particle size, stimuli-sensitivity, preventing drug efflux, solubility and permeation of the drug induce the enhanced absorption and high bioavailability. Regardless of passionate researches, some limitations still exist, for instance economic problems, toxicity issue, and development of biopharmaceutic oral nanomedicine. In this review, physiological barriers in oral administration, advantages of nanomedicines, classification of oral nanomedicines, and their challenges are described concisely.

Development of a robust ph-sensitive polyelectrolyte ionomer complex for anticancer nanocarriers

A polyelectrolyte ionomer complex (PIC) composed of cationic and anionic polymers was developed for nanomedical applications. Here, a poly(ethylene glycol)–poly(lactic acid)–poly(ethylene imine) triblock copolymer (PEG–PLA–PEI) and a poly(aspartic acid) (P[Asp]) homopolymer were synthesized. These polyelectrolytes formed stable aggregates through electrostatic interactions between the cationic PEI and the anionic P(Asp) blocks. In particular, the addition of a hydrophobic PLA and a hydrophilic PEG to triblock copolyelectrolytes provided colloidal aggregation stability by forming a tight hydrophobic core and steric hindrance on the surface of PIC, respectively. The PIC showed different particle sizes and zeta potentials depending on the ratio of cationic PEI and anionic P(Asp) blocks (C/A ratio). The doxorubicin (dox)-loaded PIC, prepared with a C/A ratio of 8, demonstrated pH-dependent behavior by the deprotonation/protonation of polyelectrolyte blocks. The drug release and the cytotoxicity of the dox-loaded PIC (C/A ratio: 8) increased under acidic conditions compared with physiological pH, due to the destabilization of the formation of the electrostatic core. In vivo animal imaging revealed that the prepared PIC accumulated at the targeted tumor site for 24 hours. Therefore, the prepared pH-sensitive PIC could have considerable potential as a nanomedicinal platform for anticancer therapy.

Development of a new tri-block copolymer with a functional end and its feasibility for treatment of metastatic breast cancer

We have developed nanomedicine vehicle based on a biocompatible tri-block copolymer, poly(ethylene glycol)-block-poly(lactic acid)-block-poly(ethylene glycol) (PEG-PLA-PEG) by simple approach without toxic linker to escalate therapeutic efficacy of anticancer agent by enhanced targeting to metastasized breast cancers. The synthesized ABA type copolymer had a low polydispersity index and formed small, highly stable spherical micelles. Furthermore, a functional group at the end site of the copolymer can be decorated with imaging agents and targeting moieties. The doxorubicin loaded micelles (DLM) showed higher drug-loading capacity, faster drug release, and better cell toxicity compared to those using di-block copolymers. DLM efficiently delivered to the metastatic breast cancers in brain and bone and suppressed growing of metastasis. In demonstration of treating metastasized animal model, we present a tri-block copolymer as a potential nanomedicine vehicle to efficiently deliver anticancer drug and to effectively treat metastatic breast cancer.

Recent advance of pH-sensitive nanocarriers targeting solid tumors

AbstractpH sensitive nanocarriers have showed the tumor targeted drug delivery and release by enhanced permeability and retention effect and responsiveness of acidic pH conditions of the solid tumors. The protonation and deprotonation of the nanocarriers including pH sensitive polyelectrolytes has been considered as a major mechanism, resulting in substantial conformational change in response to marginal change in the tumor pH conditions. Considering the biocompatible properties for pharmaceutical applications, poly(amino acid) showed low polymer toxicity and the formation of versatile systems for advanced antitumor therapeutic effects. In here, recent researches using cationic (histidine, lysine, and arginine), anionic (aspartic acid and glutamic acid), and zwitterionic amino acid were summarized. Furthermore, pH sensitive nanogels with unique functionality and other pH sensitive polymers were briefly described. pH sensitive nanogels showed reversible drug release by pH cyclization minimizing drug loss and enhancing drug release. In the future, non-spherical pH sensitive nanocarriers would be anticipated to improve the therapeutic effect by long circulation and stealth effect by low phagocytosis.

A stable nanoplatform for antitumor activity using PEG-PLL-PLA triblock co-polyelectrolyte

Polyelectrolyte has been proposed as an efficient approach for various types of drug formulations. However, one drawback of using the conventional polyelectrolyte for drug delivery is its dissociation in in vivo conditions by counter ions due to the lack of self-assembling aggregation force. In this study, we reported a stable nanoplatform based on triblock co-polyelectrolyte composed of a poly(ethylene glycol), poly(l-lysine), and poly(lactic acid). These co-polyelectrolytes formed stable aggregates through the hydrophobic interaction of PLA and showed consistent particle sizes under a high salt concentration. In addition, the doxorubicin (Dox) loaded triblock co-polyelectrolyte demonstrated enhanced cellular uptake and drug cytotoxicity with a positive charge from the poly(l-lysine) layer. In vivo, the triblock aggregates exhibited intensive accumulation at the targeted tumor site for 24h with good antitumor therapeutic efficacy. Therefore, the prepared stable triblock co-polyelectrolyte may have considerable potential as a nanomedicinal platform for anticancer and multi-drug combination therapy.

Synergistic photodynamic therapeutic effect of indole-3-acetic acid using a pH sensitive nano-carrier based on poly(aspartic acid-graft-imidazole)-poly(ethylene glycol)

Poly(aspartic acid-graft-imidazole)-poly(ethylene glycol) (P(Asp-g-Im)-PEG) was utilized as a pH-sensitive nanocarrier of the photosensitizer indole-3-acetic acid (IAA) for the treatment of skin cancer. IAA loaded micelles (ILMs) exhibited the formation of ca. 140 nm spherical particles at pH 7.4. The micelles disintegrated at acidic pHs, resulting in pH-dependent IAA release and cytotoxicity. Treatment of ILMs with visible light at a wavelength of 480 nm caused pH dependent synergistic cell damage in both in vitro and in vivo models using the B16F10 melanoma cell line. Interestingly, ILMs synergistically produced reactive oxygen species (ROS) at an acidic pH of 6.5 with visible light irradiation by proton coupled electron transfer (PCET). The pH sensitive ILMs could be considered a potent nanomedicine used to exert synergistic photodynamic therapeutic effects to treat cancers.

A charge-reversible nanocarrier using PEG-PLL(- g -Ce6, DMA)-PLA for photodynamic therapy

A polyelectrolyte nanoparticle composed of PEG-PLL(-g-Ce6, DMA)-PLA was developed for nanomedicinal application in photodynamic therapy. These nanoparticles formed stable aggregates through the hydrophobic interaction of poly(lactic acid) and demonstrated pH-dependent behaviors such as surface charge conversion and enhanced cellular uptake at acidic pH, resulting in improved phototoxicity. In vivo animal imaging revealed that the prepared PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles effectively accumulated at the targeted tumor site through enhanced permeability and retention effects. Reversible surface charge for PEG-PLL (-g-Ce6, DMA)-PLA nanoparticles allows the nanoparticles to escape the immune system and concentrate on the tumor tissue. Tumor growth in the nude mice treated with the nanoparticles decreased significantly and the hydrophobic interaction in the poly(lactic acid) block could allow the incorporation of multiple drugs. Therefore, the PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles could have considerable potential as a nanomedicinal platform for photodynamic therapy.

In Vivo Tracking of Mesenchymal Stem Cell in Rat Genitalia with Erectile Dysfunction Labeled by Superparamagnetic Iron Oxide Using Magnetic Resonance Imaging and Its Therapeutic Effect

Background: Molecular imaging with nanoparticles makes non-invasive monitoring of target cells without sacrifice of subjects and repeated evaluation possible. Objectives: To evaluate the imaging feasibility of a rat animal model with erectile dysfunction (ED) by bilateral cavernosal nerve injury using human mesenchymal stem cells (MSCs) labeled with superparamagnetic iron oxide (SPIO) and simultaneously to evaluate the beneficial effect of MSCs on ED. Materials and Methods: Thirty-six rats were injected with MSCs labeled with SPIO particle into the corpus cavernosum after bilateral cavernosal nerve injury. In vivo MR imaging was serially performed up to 16 weeks using 1.5 T clinical scanner. After MR imaging, the penile specimens were evaluated for the expression of transforming growth factor-β1 (TGF-β1) by polymerase chain reaction. Results: MR imaging showed a drop in signal intensity at the injection site in the stem cell-injected group. The size of hypointensity was decreased in MSC-injected group in a time-dependent manner; whereas, signal void was not detected at the injection site in the control group. In addition, polymeric chain reaction (PCR) analyses of penile tissues from both groups revealed that the mRNA expression of TGF-β1 was significantly decreased in MSC-injected groups after 4 weeks of injection compared to the control group. Conclusion: MSCs’ beneficial effects on ED was monitored with MR imaging, which might be a valuable tool for tracking and therapeutic monitoring in the future clinical study of stem cell therapy in ED.

Cyclic RGD-conjugated Pluronic ® blending system for active, targeted drug delivery

Background Blending micellar systems of different types of polymers has been proposed as an efficient approach for tailor-made drug formulations. The lamellar structure of hydrophobic polymers may provide a high drug loading capacity, and hydrophilic polymers may provide good colloidal stability. Methods In this study, the anticancer model drug docetaxel was loaded onto a nanosized blending micellar system with two pluronics (L121/F127). To achieve increased antitumor activity, the cyclic arginine-glycine-aspartic acid tripeptide (cRGD) as an active tumor targeting ligand was conjugated to the blending system. Results The docetaxel-loaded Pluronic blending system exhibited a higher drug loading capacity than that of F127 and showed high colloidal stability with a spherical structure. cRGD conjugates demonstrated enhanced drug cellular uptake and anticancer activity against αvβ3 integrin-overexpressing U87MG cancer cells. In vivo animal imaging also revealed that the prepared cRGD-conjugated nanoparticles effectively accumulated at the targeted tumor site through an active and passive targeting strategy. Conclusion Accordingly, the prepared nanosized system shows potential as a tailor-made, active targeting, nanomedicinal platform for anticancer therapy. We believe that this novel nanoplatform will provide insights for advancement of tumor therapy.