Micelles, anticancer drugs

Polymer micelles are nanometer sized (usually several tens of nanometers) self-assembled particles having a hydrophobic core and hydrophilic outer shell composed of amphiphilic AB- or ABA-type block copolymers, and are utilized as drug delivery vehicles. The first polymer micelle-type drug delivery vehicle was made of PEG-b-poly(aspartic acid) (PEG-b-PAsp), immobilizing the hydro-phobic anticancer drugDXR [188-191]. After this achievement by Kataoka et al., a great amount of research on polymer micelles has been carried out, and there are several reviews available on the subject [192-194]. 

As described above, the most common hydrophilic polymer combined with aliphatic polyesters to prepare polymer micelles is PEG. Although there have been many reports on the polymer micelles of PEG-b-aliphatic polyesters, only few recent examples are introduced in this review. Shin et al. reported the therapeutic potential of PEG-b-PLA micelles entrapping multiple anticancer drugs of poor solubility in... 

Yokoyama M, Okano T, Sakurai Y, Ekimoto H, Shibazaki C, Kataoka K (1991) Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. Cancer Res 51 3229-3236... 

Yokoyama, M., Miyauchi, M., Yamada, N., Okano, T., Sakurai, Y, Kataoka, K., and Inoue, S. Characterization and anticancer activity of the micelle-forming polymeric anticancer drug adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. Cancer Res., 1990, 50, 1693-1700. 

Polymeric micelles are mostly small (10-100 nm) in size and dmgs can be incorporated by chemical conjugation or physical entrapment. For efficient delivery activity, they shonld maintain their integrity for a sufficient amount of time after injection into the body. Most of the experience with polymeric micelles has been obtained in the field of passive targeting of anticancer drugs to tumours [33]. Attachment of antibodies or sugars, or introduction of a polymer sensitive to variation in temperature or pH has also been stndied [32]. 

In addition to the hydrophobic interaction mentioned above to encapsulate guest molecules, other types of nonspecific interactions have also been explored to enhance binding. For example, block copolymer micelles based on PEO as hydrophilic segments and poly(/3-benzyl L-aspartate) as hydrophobic blocks have used to encapsulate doxombicin. The encapsulation efficiency of doxombicin, an aromatic anticancer drug molecule, has been found to be significantly higher. This observation has been attributed to the tt-tt interaction between the anthracycUne moiety of doxorubicin and the benzyl group of poly(/3-benzyl L-aspartate) (Cammas-Marion et al. 1999). 

Yokoyama, M., A. Satoh, Y. Sakurai, T. Okano, Y. Matsumara, T. Kakizoe, and K. Kataoka. 1998. Incorporation of water-insoluble anticancer drug into polymeric micelles and control of their parti cl eJsSentrol. 

Bontha, S., et al. (2006), Polymer micelles with cross-linked ionic cores for delivery of anticancer drugs,/. Controlled Release, 114(2), 163-174. 

Polymeric micelles were developed as a tumor-targeted delivery system for poorly water-soluble and toxic anticancer drugs. Preclinical studies have demonstrated reduced toxicity and enhanced accumulation of drugs in tumors with polymeric micelle systems. Issues such as sufficient in vivo stability and programmable drug release at the tumor sites need to be addressed in the future. 

Gao, Z. G., Lukyanov, A. N., Singhal, A., Torchilin, V. P. Diacyl-lipid polymer micelles as nanocarriers for poorly soluble anticancer drugs. Nano Lett. 2002, 2, 979-982. 

Many of the poorly soluble drugs included in amphiphilic chitosan-based nanocarriers are anticancer drugs, e.g., paclitaxel, doxorubicine, camptothecin, and Mytomycin C. Besides increasing their solubility, the polymeric micelles... 

Figure 6 (a) Schematic presentation of polymeric nanoparticles with weak acid (sulfonamide groups). The polymeric nanoparticles show good stabdity at pH 7.4 but are aggregated/shrunken near the tumor where the pH is below tumor pHg. (b) A schematic concept of anticancer drug release triggered by the change of hydrophobic core solubility in the polymeric micelle. 

Figure 24 (a) A proposed new carrier for switching the release of an anticancer drug by early endosomal pH from polymeric micelles and (b) the polymeric micelles for effective anticancer drug delivery to MDR cells with receptor-mediated endocytosis, switching release rate, and fusogenic activity of polymeric micelle components. 

Figure 4 Interaction between metal-complex anticancer drugs, cisplatin (CDDP), and the core-forming segments of the block copolymers PEG-P(Asp) and PEG-P(Glu). The methane group in the side chain of PEG-P(Glu) was reported to play an important role in significantly increasing the stabihty of the micelles compared to PEG-P(Asp).

Figure 8 An example of the intracellular environment-sensitive polymeric micelles. The anticancer drugs known as Adriamycin are clustered to a core-forming segment of the block copolymers through acid-sensitive bonds. Prepared micelles can release the loaded drugs by responding to pH decrease within intracellular compartments such as endosomes and lysosomes.

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