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Multimolecular-Assembly of Smart Block Copolymers as Nanocarrier for Gene and Drug Delivery

Kazunori Kataoka
Center for NanoBio Integration Department of Materials Engineering and Center for Disease Biology and Integrative Medicine, The University of Tokyo. Hongo, Tokyo. Japan

 

Polymeric micelles, self-assemblies of block copolymers, are promising nanocarrier systems for drug and gene delivery. Several micellar formulations of antitumor drugs have been intensively studied in preclinical and clinical trials, and their utility has been demonstrated. Even compared with long-circulating liposomes, polymeric micelles might have several advantages, such as controlled drug release, tissue penetrating ability and reduced toxicity such as hand–foot syndrome and hypersensitivity reaction. Importantly, critical features of the polymeric micelles as drug carriers, including particle size, stability, and loading capacity and release kinetics of drugs, can be modulated by the structures and physicochemical properties of the constituent block copolymers. The development of smart polymeric micelles that dynamically change their properties due to sensitivity to chemical or physical stimuli is the most promising trend, directing to the targeting therapy with high efficacy and ensured safety [1].

In this way, smart polymeric micelles can respond to pathological or physiological endogenous stimuli already present in the body or to externally applied stimuli such as temperature, light or ultrasound. One sophisticated and rational approach is the increased hydorophobicity of the core of the polymeric micelles loaded with platinum-based drug to modulate the drug releasing profile triggered by chloride ion in the body fluid so as to have a sufficient induction period, avoiding the systemic drug leakage and achieving the selective and sustained drug release at the site of solid tumor [2]. According to this strategy, DachPt-loaded micelle was recently developed to show further longevity in blood circulation as well as improved anticancer effect compared to cisplatin-loaded polymeric micelles [3].

pH-triggered system has also a great promise in the treatment of intractable cancers. Here, the therapeutic agent should be stably associated with the hydrophobic core, and the release of the drug will be expected to occur along with the destabilization of the micelle structure responding to acidic pH of tumor tissue as well as intracellular compartment such as endosome and lysosome [4]. Notable anti-tumor efficacy against hypovascular cancer, including pancreatic cancer and diffused-type stomach cancer, of the doxorubicin-incorporated polymeric micelles with pH-responding property was demonstrated to emphasize a promising utility of DDS for the treatment of intractable cancers [5]. Photodynamic therapy (PDT), which involves the systemic administration of photosensitizers (PSs) and the following photoirradiation to the diseased sites, is a promising physical approach for the cancer treatment. However, it is known that PSs are easily form aggregates, resulting in reduction of the singlet oxygen production significantly. To prevent the self-quenching of PS, ionic dendritic PS (DPs) were prepared, and incorporated into the polymeric micelles [6]. Eventually, the DP-loaded micelles showed a significant increase in the photocytotoxicity compared to free DP, achieving a remarkable photodynamic efficacy against subcutaneous tumor model in experimental animals by systemic injection.

The success in gene and nucleic acid delivery indeed relies on the development of the safe and effective carriers. In this regard, polyion complex (PIC) micelles, which are formed between nucleic acid and PEG-polycation block copolymers have received much attention due to their small size (~ 100 nm) and excellent biocompatibility [7]. Recently, siRNA incorporated PIC micelle was prepared from PEG-poly(lysine) block copolymer with SH groups in the side chain [8]. This PIC micelle is expected to release loaded siRNA selectively in cytoplasm due to the cleavage of disulfide crosslinking responding to the reductive intracellular environment, leading to the effective silencing of target gene related to oncogenesis. In turn, the disulfide crosslinking is stable enough in blood compartment to achieve prolonged circulation because of oxidized atmosphere in the body. Furthermore, facilitated endosomal escape occurs in the PIC micelle having intermediated layer between shell and core phase to exert the selective destablization of endosomal membrane through proton sponge effect as well as direct perturbation of the membrane structure [9]. These PIC micelles loading plasmid DNA or siRNA are now moving into in vivo evaluation for future molecular therapy.

 

References:

[1] N. Nishiyama, K. Kataoka, Current state, achievements, and future prospects of polymeric micelles as nanocarriers for drug and gene delivery. Pharmacol. & Ther. 112 (3) 630-648 (2006)

[2] H. Cabral, N. Nishiyama, S. Okazaki, H. Koyama, K. Kataoka, Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles. J. Control. Release 101 (1-3) 223-232 (2005)

[3] H. Cabral, N. Nishiyama, K. Kataoka, Optimization of (1,2-diamino-cyclohexane)platinum(II)-loaded polymeric micelles directed to improved tumor targeting and enhanced antitumor activity. J. Control. Release 121 (3) 146-155 (2007)

[4] Y. Bae, S. Fukushima, A. Harada, K. Kataoka, Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew. Chem. Int. Ed. 42 (38) 4640-4643 (2003)

[5] M. R. Kano, Y. Bae, C. Iwata, Y. Morishita, M. Yashiro, M. Oka, T. Fujii, A. Komuro, K. Kiyono, M. Kamiishi, K. Hirakawa, Y. Ouchi, N. Nishiyama, K. Kataoka, K. Miyazono, Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. P. Natl. Acad. Sci. USA. 104 (9) 3460-3465 (2007)

[6] H. R. Stapert, N. Nishiyama, D. -L. Jiang, T. Aida, K. Kataoka, Polyion complex micelles encapsulating light-harvesting ionic dendrimer zinc porphyrins. Langmuir 16 (21) 8182-8188 (2000)

[7] K. Kataoka, H. Togawa, A. Harada, K. Yasugi, T. Matsumoto, S. Katayose, Spontaneous formation of polyion complex micelles with narrow distribution from antisense oligonucleotide and cationic block copolymer in physiological saline. Macromolecules 29 (26) 8556-8557 (1996)

[8] S. Matsumoto, R. J. Christie, N. Nishiyama, K. Miyata, A. Ishii, M. Oba, H. Koyama, Y. Yamasaki, K. Kataoka, Environment-responsive block copolymer micelles with a disulfide cross-linked core for enhanced siRNA delivery, Biomaromolecules, in press

[9] K. Miyata, M. Oba, M. R. Kano, S. Fukushima, Y. Vachutinsky, M. Han, H. Koyama, K. Miyazono, N. Nishiyama, K. Kataoka, Polyplex micelles from triblock copolymers composed of tandemly aligned segments with biocompatible, endosomal escaping, and DNA-condensing functions for systemic gene delivery to pancreatic tumor. Pharm. Res. in press