OCTOBER 2009 Volume 20, Number 10
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Copyright 2009 by the American Chemical Society
COMMENT Intelligent Drug Delivery Systems Yu-Kyoung Oh School of Pharmacy, Seoul National University, Sinlim-dong, Kwanak-gu, Seoul 151-742, South Korea
Peter D. Senter Seattle Genetics, 21823 30th Drive SE, Bothell, Washington 98021
Soo-Chang Song Division of Life Science, Korea Institute of Science and Technology, Seoul 130-650, South Korea. Received June 12, 2009; Revised Manuscript Received July 28, 2009
There has been a great deal of research in recent years toward improving drug delivery and selectivity through the use of macromolecular-based drug carriers such as monoclonal antibodies, liposomes, polymers, dendrimers, micelles, and hydrogels (1-3). These areas were featured at the 2009 International Symposium on Intelligent Drug Delivery Systems that was held at the Korea Institute of Science and Technology (KIST) in Seoul, South Korea on April 29-30, 2009. The meeting was sponsored by the Korean Ministry of Education, Science and Technology and the Korea Biotech R & D Group in an initiative to promote drug delivery research within the country. We felt that readers of Bioconjugate Chemistry would be interested in several of the presentations at the meeting, given the relevance to the scope of the journal. Kinam Park from Purdue University provided a keynote address entitled “Practical nanotechnology and microfabrication for drug delivery” (4). The history of drug delivery systems was overviewed, beginning with examples of the first delayed and sustained release technologies in the 1950s and 1960s, through the development of nanotechnologies that are under active investigation. This has led to the approval of several macromolecular-based drugs such as Doxil, Abraxane, and Genexol for cancer therapy (3). “Smart polymers” and newer *
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materials allow for controlled released of drugs under specific conditions (5). Advancements in material science has allowed for the production of solid supports for drug delivery in which imprinting technologies are used to produce novel scaffolds for drug attachment and controlled release (6). Several of the issues are being resolved including biocompatibility, scale-up, drug loading, and control of release kinetics. Some elegant examples of such technologies were provided by Ping Lee at the University of Toronto who described the development of osmotic tablets which are used in more than 20 approved drugs. Other delivery systems of great interest include osmotically driven miniaturized implants, hydrogel capsules, polymeric drug derivatives, and inhalable formulations (7). While these technologies may offer significant advantages over current formulations, the regulatory, cost, and compliance issues are significant. Nanotechnology-based drug delivery systems were described that allow for both spatial and temporal control of drug release. Yongdoo Park from Korea University described biomimetic hydrogels that not only allowed for controlled drug release, but also could be devised to release mechanistically distinct drugs in a sequential manner (8). In a complementary approach, Keun-Hong Park from CHA University in Seoul described a dual drug delivery strategy involving a nanoparticle consisting of a drug-loaded poly(lactic acid)-poly(glycolic acid) copolymer (PLGA) with ionically associated drug-polyethyleneimine complexes (9). These
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novel carriers allowed for dual drug release in vivo over extended time periods. Kazuo Maruyama from Teikyo University in Japan described the preparation of liposomes containing perfluoropropane bubbles together with anticancer drugs, siRNA, or proteins of therapeutic interest (10). Upon exposure to ultrasonic radiation, the exploding bubbles disrupted liposomal structure, leading to drug release. The technology was applied to the delivery of antigens to dendritic cells for active tumor immunotherapy. Tatsuhiro Ishida from the University of Tokushima in Japan described how liposomal drug formulations can be used in combination with systemic drug therapy in metronomic therapeutic protocols. Low and frequent dosing regimens of various liposomal and free drug combinations resulted in pronounced intratumoral drug delivery and therapeutic efficacy (11). The meeting featured talks on drug formulations that greatly extend the use and activities of clinically approved agents. HanGon Choi from Yeungnam University in Korea described how a solid dispersion system of poorly soluble drugs such as paclitaxel, valsartan, and tacrolimus improved drug solubility and pharmacologic properties such as AUC, Cmax, and Tmax values (12). Another example was provided by Han-Kwang Yang from Seoul National University who described the effects of biodegradable, thermosensitive hydrogels for drug encapsulation and release (13). Preparations were described that allowed for in vivo anticancer drug release over a period of 50 days, and these led to pronounced activity over systemic chemotherapy. It was possible to use such preparations for direct intratumoral injection. Doo Sung Lee from the Sungkyunkwan University in Suwon, South Korea, discussed pH-responsive micelles for therapy and diagnostics (14). Carboxylic acids were incorporated into the hydrophilic backbone of drug-loaded micelles, and upon acidification below pH 6.8, disruption of the micelle structure led to rapid and quantitative drug release. Pronounced therapeutic efficacy was obtained in tumor xenograft models. The technology was extended to include imaging agents, which were applied to both cancer and stroke indications. While it is widely known that macromolecules penetrate slowly through solid tumors, little is known about low molecular weight anticancer drugs. Hyo-Jeong Kuh from the Catholic University in Korea utilized three-dimensional multicellular layer and spheroid models to track the penetration of doxorubicin, paclitaxel, and siRNA into tumors (15, 16). She found that penetration were functions of both the drug and the tumor model being tested. In some cases, penetration was uniform, but in other cases, it was biphasic. This type of work could provide insight into the development of synergistic drug combinations acting on tumor cells that are either near or distal to vascular beds. The power of attacking distinct cell populations was illustrated by Tae Woo Kim from Korea University, who demonstrated that large tumor masses could be eradicated using a multimodality approach that included anticancer drugs combined with agents that stimulate tumor-specific CD8 positive cells (17). Claude Meares from the University of California at Davis provided the other keynote address in a presentation that overviewed radioimmunotherapy targeting technologies. An approach that has been clinically validated involves pretargeting, exemplified by antibody-streptavidin fusion protein administration, followed by a biotin-macrocyclic metal chelating agent, DOTA, radiometal chelate. This approach circumvents extensive radiation exposure to normal tissues, since the biotin-DOTA complex is rapidly cleared (18). The technology was extended to include genetically engineered antibodies with cysteine residues near the antigen binding sites that form covalent adducts with an electrophilic form of the DOTA hapten. These antibodies were referred to as antibodies with infinite affinity (19, 20). A variant of this technology included the imaging of tumors in vivo that were transfected with the cysteine-mutated antibodies.
Oh et al.
Felix Kratz from the Tumor Biology Center in Freiburg, Germany, described a novel form of anticancer drug delivery involving the administration of anticancer drugs that contain appended maleimides that form covalent bonds with cysteine34 in albumin (21, 22). This leads to a macromolecule that has much longer circulating times than the free drug and has the ability to penetrate into tumors. The drug can be released from albumin through acid-mediated or enzymatic hydrolysis, depending on the linker system used. This is a versatile technology that allows for multidrug and targeted delivery approached. The lead agent, 6-maleimidocaproyl hydrazone derivative of doxorubicin (doxorubicin-EMCH), has provided evidence of response in early stage clinical testing. Peter Senter from Seattle Genetics utilized monoclonal antibodies for the delivery of highly potent drugs such as auristatins to tumors (23-25). The results from a phase I clinical trial demonstrated that 86% of patients with CD30 positive lymphomas experienced tumor reduction, which included complete and partial remissions. The results underscore the importance of drug potency, linker stability, and tumor selectivity in generating therapeutically effective drug conjugates for cancer therapy. This work was extended by Qiang Zhang from Peking University, China, to include the delivery of TNFR to tumors by administration of PEG-peptide-TNFR that could be cleaved by tumor-associated proteases. The conjugates with the cleavable linker were more active than those without. One of the central aspects involved in drug delivery includes technologies for adhering drugs to the carriers of interest. Haeshin Lee from the Korea Advanced Institute of Science and Technology described adhesive molecules derived from those used by mussels for sticking to solid surfaces in water (26, 27). A series of catechol derivatives were able to form cross-links in water through either oxidative addition or through metal chelation chemistry. These agents were used to adhere proteins to surfaces for use in capturing cells through receptor-mediated interactions. In summary, the 2009 International Symposium on Intelligent Drug Delivery Systems featured research in areas of great promise for new therapeutics. In particular, new micellar, liposomal, and hydrogel formulations allow for extended drug release, and new applications of water-insoluble drugs that are otherwise difficult to administer. Developments in nanotechnologies have produced materials that release drugs in a sequential manner or release complementary drugs under welldefined conditions. Specific targeting has advanced significantly, with clinically effective antibody-drug and radionuclide conjugates. Some of the challenges that lie ahead were illustrated by Hiroshi Kikuchi from Eisai Corporation in Japan and Kuchan Kimm of MSD Korea, the Korean branch of Merck & Co., both of whom discussed the difficulties in getting novel and expensive agents like those described in the meeting approved and widely utilized. However, as these agents progress through clinical trials and demonstrate activity beyond what is achievable with conventional agents, it is expected that they will comprise the drugs of the future. The next meeting will be held in May, 2010, at KIST in Seoul, South Korea.
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