Taehoon Sim

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.

A feasibility study of a pH sensitive nanomedicine using doxorubicin loaded poly(aspartic acid-graft-imidazole)-block-poly(ethylene glycol) micelles

A polyelectrolyte block copolymer, poly(aspartic acid-graft-imidazole)-block-poly(ethylene glycol) (P(Asp-g-Im)-PEG), with several advantages such as an easy synthesis, having a high molecular weight and the buffer capacity of a zwitterionic polymer backbone compared to poly(histidine) backbones, was presently investigated to evaluate its feasibility as a pH sensitive anticancer nanomedicine. Doxorubicin (DOX) loaded P(Asp-g-Im)-PEG micelles (DPHAIM) were prepared by the bottom flask and diafiltration methods, forming stable pH sensitive nano-systems. DPHAIM with a 28% loading capacity displayed a pH dependent behavior with respect to drug release and cytotoxicity. At pH values below 7.0, the cumulative DOX release and cell cytotoxicity were increased compared to those at physiological pH. Animal imaging after intravenous administration of the micelles revealed their accumulation by passive targeting to tumor tissue compared to other normal tissues. This pH sensitive nanovehicle based on P(Asp-g-Im)-PEG is implicated as a promising anticancer nanomedicine with less toxicity on normal tissues for effective tumor treatment.

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.

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.

Characterization and pharmacokinetic study of itraconazole solid dispersions prepared by solvent-controlled precipitation and spray-dry methods

Solid dispersion formulations have attracted attention to improve solubility and bioavailability of water‐insoluble drugs. In this study, the variation of solubility and bioavailability by different preparation methods were studied using itraconazole (ITZ) solid dispersions.

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.

Development of a gene carrier using a triblock co-polyelectrolyte with poly(ethylene imine)-poly(lactic acid)-poly(ethylene glycol)

The success of gene therapy mainly depends on the carriers for effective gene delivery. A non-viral vector using a cationic block co-polyelectrolyte, PEI-PLA-PEG polyethyleneimine-poly(lactic acid)-poly(ethylene glycol)) was developed as a potential gene carrier. The cationic PEI-PLA-PEG showed less toxicity compared to PEI and formed a gene nanocomplex (termed polyplex) by interaction with plasmid DNA or small interference RNA. The polyplex showed smaller particle size and greater positive zeta potential by increasing the high polymer nitrogen/DNA phosphate ratio. The polyplex with a nitrogen/DNA phosphate ratio of 16 or 32 demonstrated higher gene transfection by fluorescence imaging, flow cytometry measurement, and β-galactosidase activity. In particular, the polyplex with therapeutic histone deacetylase small interference RNA at nitrogen/DNA phosphate ratio 16 showed the most favorable properties with definite tumor growth inhibition. The synthetic PEI-PLA-PEG also showed less toxicity and would, therefore, be a great potential gene carrier, particularly given that small interference RNA delivery does not increase the charge density of small interference RNA due to the formation of a stable complex through conjugation with PLA-PEG.

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.