Anticancer drugs targeted delivery

Figure 8.18 (a) An example of folic acid conjugated with PU, using LDI, and 1,5-pentane diol based PU-urea system, (b) PU-conjugated anticancer drug (oxaplatin) delivery to specific lactose receptor, overexpressed in cancer cells. Lactobionic acid (targeting moiety). 

Ultimately, for Pt(IV) anticancer drugs, a combination of incorporation of bioactive ligands that specifically target cancer cells, control over ligand-exchange kinetics, and selective activation by light would allow for temporal and spatial control of drug delivery and activation. 

A major point that needs to be addressed in future work is the targeted delivery of organometallic anticancer drugs to cancer cells only. Also, additional features that generate cytotoxic activity other than disruption of DNA replication, such as the inclusion of molecular fragments that can interfere in cancer cell-specific cellular pathways, could be explored (11,103). 

Dufes, C., J. M. Muller, W. Couet, J. C. Olivier, I. F. Uchegbu, and A. G. Schatzlein. 2004. Anticancer drug delivery with transferrin targeted polymeric chitosan vesicles. Pharm Res 21(l) 101-7. 

Several types of dmg carriers such as microspheres, liposomes, and polymer have been investigated to achieve targetable drug delivery, especially for anticancer drugs. However, nonselective scavenging of such carriers by the reticuloendothelial system (RES) is a serious problem even when monoclonal antibodies are used to carry the dmg [15,16]. 

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]. 

The experiments reviewed in Section 13.1 demonstrated in detail that LCM can be labeled with lipophilic fluorescent dye and still retain their tumor-targeting properties. Furthermore, these lipophilic-dye-labeled LCM were shown to become internalized by tumor cells both in vitro and in vivo. This tumor-targeting ability of dye-labeled LCM, and their in vivo persistence at the tumor site and/or within the tumor cell for many minutes, suggested a potential use of LCM as a targeted drug-delivery agent or vehicle (ref. 532). Thus, a search was started for lipophilic anticancer drugs (preferably already FDA-approved for clinical use) that could be incorporated into the LCM and carried specifically to the tumor site. 

Figure 5.28. Bowtie dendrimer synthesized via the convergent approach, for drug delivery of anticancer drugs to target organs. Reproduced with permission from Gillies, E. R. Dy, E. Frechet, J. M. J. Szoka, F. C.Mol. Pharm., 2005, 2, 129. Copyright 2005 American Chemical Society.

A nanoparticle is a microscopic particle with a diameter less than 100 nm. Nanoparticles were first developed around 1970, and initially they were devised as carriers for vaccines and anticancer drugs. Nanoparticle research is currently an area of intense scientific research because of a wide variety of potential applications in biomedical, optical, and electronic fields. To enhance tumor uptake, the strategy of drug targeting was employed, and as a first important step, research focused on the development of methods to reduce the uptake of the nanoparticles by the RES cells. Simultaneously, the use of nanoparticles for ophthalmic and oral delivery was investigated (17, 18). Recent advancement of nanoparticles and nanosuspensions was caused by their application for pulmonary drug delivery (19, 20). 

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. 

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