Preclinical and clinical studies of anticancer agent‐incorporating polymer micelles

Abstract

The size of anticancer agent-incorporating micelles can be controlled within the diameter range of 20-100 nm to ensure that they do not penetrate normal vessel walls. With this development, it is expected that the incidence of drug-induced side-effects may be decreased owing to the reduced drug distribution in normal tissue. Micelle systems can also evade non-specific capture by the reticuloendothelial system because the outer shell of a micelle is covered with polyethylene glycol. Consequently, a polymer micelle carrier can be delivered selectively to a tumor by utilizing the enhanced permeability and retention effect. Moreover, a water-insoluble drug can be incorporated into polymer micelles. Presently, several anticancer agent-incorporating micelle carrier systems are under preclinical and clinical evaluation. Furthermore, nucleic acid-incorporating micelle carrier systems are also being developed. (Cancer Sci 2009; 100: 572-579) N anotechnology is one of the fast-moving technologies and is presently contributing significantly to the progress of medical science. Drugs categorized under the drug delivery system (DDS) are made primarily by utilizing nanotechnology. In the field of oncology, DDS drugs have been produced and evaluated in preclinical or clinical trials, with some already approved for clinical use (Table 1). More specifically, DDS can be used for active or passive targeting of tumor tissues. Passive targeting refers to the development of monoclonal antibodies directed against tumor-related molecules, allowing targeting of a tumor from the specific binding of antibodies with respective antigens. However, the application of DDS using monoclonal antibodies is restricted to tumors expressing high levels of related antigens.Passive targeting can be achieved by utilizing the enhanced permeability and retention (EPR) effect.(1,2) This effect is based on the pathophysiological characteristics of solid tumor tissues, namely, hypervascularity, incomplete vascular architecture, secretion of vascular permeability factors stimulating extravasation within cancer tissue, and absence of effective lymphatic drainage from tumors that impedes the efficient clearance of macromolecules accumulated in solid tumor tissues (Fig. 1A,B).Several techniques have been developed to maximally utilize the EPR effect such as modification of drug structures and development of drug carriers. Polymeric micelle-based anticancer drugs were originally developed by Kataoka et al. in the late 1980s or early 1990s. (3-5) Polymeric micelles were expected to increase the accumulation of drugs in tumor tissues by utilizing the EPR effect as well as to incorporate various kinds of drugs into their inner core with relatively high stability by chemical conjugation or physical entrapment. Also, the size of micelles can be controlled within the diameter range of 20-100 nm to ensure that they do not penetrate normal vessel walls. With this development, it is expected that the incidence of drug-induced side-effects may be decreased owing to the r...

Peptide-Based Polymer Therapeutics

“…Polymer Therapeutics includes five different groups: polymeric drugs, polymers with inherent activity [5,6] polymer-protein conjugates [3,7,8]; polyplexes which are multi-component systems developed as non-viral vectors for gene/small interfering ribonucleic acid (siRNA) delivery [9,10], polymeric micelles where the bioactive agent is covalently bound [11,12] and polymer-drug conjugates [3] ( Figure 1). This field has been exhaustively revised and the following background references are recommended [4,[13][14][15].…”

A pH-sensitive multifunctional gene carrier assembled via layer-by-layer technique for efficient gene delivery

“…It was demonstrated that intratumoral pH value in solid tumors was around 6.5. 50 Therefore, in the in vitro transfection test, the pH value of cell culture medium without serum was adjusted to 6.5 to mimic the acidic microenvironment of tumor cells. It was found that CMCS-CLDPD achieved similar transfection efficiency to CLDPD at pH 6.5 but with lower transfection efficiency at pH 7.4 ( Figure 13).…”

In vivo pharmacokinetics, biodistribution and antitumor effect of paclitaxel-loaded micelles based on α-tocopherol succinate-modified chitosan

“…Therefore, the polymeric micelles are considered as promising carriers of water-insoluble anticancer drugs. Currently, several promising candidates are in clinical trials (Lee et al, 2008;Matsumura & Kataoka, 2009). …”