Drug delivery to resistant tumors: the potential of poly(alkyl cyanoacrylate) nanoparticles☆
Introduction
In chemotherapy, pharmacologically active concentrations of an anticancer drug in the tumor tissue are often reached at the expense of massive contamination of the rest of the body. This poor specificity creates a toxicological problem that represents a serious obstacle to effective antitumor therapy. In addition, the occurrence of resistance phenomena increases the problem of tumor treatments. Thus, in clinics, the occurrence of multidrug resistance (MDR) may appear either as a lack of tumor size reduction or as a clinical relapse after an initial positive response to antitumor treatment [1]. As illustrated in Fig. 1, the resistance mechanism can have different origins. In the tumor tissue, it can be either directly linked to specific mechanisms developed by the tumor cells or it can be connected to the physiology of the tumor tissue, including a poor vasculature and unsuitable physicochemical conditions [2], [3], [4], [5]. Outside the tumor tissue, the resistance to chemotherapy can be due to the more general problem of the distribution of a drug relative to its targeted tissue [6]. To overcome drug resistance many attempts have been made using strategies that consider the more general problem of the control of the drug biodistribution either at the cellular level or at the tissue level [2], [7]. The purpose of this paper is to summarize the results of the use of nanoparticles to overcome MDR phenomena occurring at both the cellular and the non-cellular level. Thus, the first part will give an overview of the main results obtained with nanoparticles designed to overcome specific resistance at a cellular level. In the second part, the different nanoparticles designed to achieve a better control of the biodistribution of drugs towards tumoral tissue will be described.
Section snippets
The potential of nanoparticles to overcome multidrug resistance at the cellular level
Tumor cells can specifically develop simultaneous resistance to multiple lipophilic compounds [1], [2]. For instance, cellular resistance to anthracyclines has been attributed to an active drug efflux from resistant cells, linked to the presence of transmembrane P-glycoprotein (P-gp), which was not detectable in the parent drug-sensitive cell line [8]. As illustrated in Fig. 2, drugs such as doxorubicin appear to enter the cell by passive diffusion through the lipid bilayer. With resistant
The potential of nanoparticles to overcome multidrug resistance due to the more general problems of drug biodistribution
Potentially, nanoparticles can enhance the protection of anticancer drugs against biotransformation and rapid clearance from the body [25], [26]. In addition, nanoparticles should have the proper biodistribution to target tumor tissue and tumor cells. With these objectives, studies carried out on PACA nanoparticles have focused on the customization of their surface properties. To date, three major approaches have been explored [7], [27], [28], [29], [30] (Fig. 5). In this paper, we will focus
Conclusion
In cancer therapy, the occurrence of resistance phenomenon is a major obstacle for the treatment of tumors. PACA nanoparticles have been found to provide a useful alternative at a cellular level to overcome MDR mediated by the P-gp. These nanoparticles have been demonstrated to combine favorable drug release and biodegradation properties, while cell interactions of the carrier and its degradation products mediate the intracellular penetration of the drug. PACA nanoparticles have passed a
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Presented at 11th International Symposium on Recent Advances in Drug Delivery Systems and CRS Winter Symposium, Salt Lake City, UT, March 3–6, 2003.