1.11 Polymer based nanocarriers .1 Polymer nanoparticle
1.11.2 Polymeric Micelle
Polymeric micelles represent a separate class of nanocarriers which are formed by self- assembly from copolymers consisting of both hydrophilic and hydrophobic units. These are nanoscopic (~100 nm) spherical structures with a core-shell architecture where the hydrophobic units of the polymer form the core and hydrophilic units form the shell. They were first proposed as drug carriers in 1984 and in recent years they have emerged as potential nanocarrier of anticancer drugs for cancer therapy (Bader et al., 1984; Nishiyama and Kataoka, 2006). Thermodynamic phenomenon underlying micelle formation from amphiphilic polymers are the same as for micellization of any low molecular weight surfactants i.e. the formation of micelles is driven by the decrease of free energy in the system because of the removal of hydrophobic fragments from the aqueous environment and the reestablishing of hydrogen bond network in water. Additional energy gain results from formation of Van der Waals bonds between hydrophobic blocks in the core of the formed micelles (Jones and Leroux, 1998). The key parameter for micellization process is the critical micelle concentration (CMC) of amphiphile. At very low concentrations amphiphilic copolymers exist as single chains (unimers) in solution but as concentration increases to reach the CMC, polymer chains start to associate to form micelle nanostructures (Hernandez et al., 2005). Polymeric micelles generally exhibit a CMC value much lower than that of low molecular weight surfactants which renders them to be more suitable for drug delivery applications (Wilhelm et al., 1991). Hydrophobic core of polymeric micelles provides an excellent cargo space for the incorporation and stabilization of hydrophobic drugs whereas the shell is responsible for micelle stabilization and interactions with plasmatic proteins and cell membranes. The biodistribution of the micellar carrier is also dictated by the nature of the hydrophilic shell (Gaucher et al., 2005). It usually consists of hydrophilic, nonionic,
biocompatible polymers such as poly(ethylene glycol), poly(N-vinyl-pyrrolidone) and poly(vinyl alcohol) (Elbert and Hubbell, 1996). The nanoscopic dimension as well as unique properties offered by separated core and shell domains in the structure of polymeric micelles has made them one of the most promising carriers for passive or active drug targeting in cancer. The small size of polymeric micelles makes the carrier unrecognizable by the phagocytic cells of RES, elongating their blood circulation, and facilitating the carrier’s extravasation from tumor vasculature (Allen et al., 1999). The small size of polymeric micelles is also expected to ease penetration of the carrier within the tumor tissue and further internalization of polymeric micelles into the tumor cells (Kwon, 1998; Allen et al., 1999).
To date, two of the drugs that have been most commonly formulated in block copolymer micelles are doxorubicin and paclitaxel. Doxorubicin has been successfully loaded into micelles formed from PEG-b-poly( 3-caprolactone) (PEG-b-PCL), PEG-b-poly(D,L-lactide- co-glycolide) (PEG-b-PLGA), PEO-b-poly(propylene oxide)-b-PEO (Pluronic), and PEG-b- poly (aspartic acid) (PEG-b-PAsp) whereas, paclitaxel has been successfully loaded into PEG-b-poly(D,L-lactide) (PEG-b- PDLLA), poly(N-vinyl-pyrrolidone)-b-PDLLA (PVP-b- PDLLA), PEG-b-PCL and PEG-b-poly(d-valerolactone) (PEG-b-PVL) micelles (Shuai et al., 2004; Yoo and Park, 2001; Kwon et al., 1994; Liggins et al., 2002). Cisplatin and camptothecin were other drugs which have been formulated in micellear nanocarriers (Uchino et al., 2005; Watanabe et al., 2006).
Many preclinical fundamental studies have evaluated the relationships between the composition of the copolymers and the physico-chemical properties of the micelles. The properties of the micelles such as polymer–drug compatibility, thermodynamic and kinetic stability, and the drug release profiles have been shown to influence the in vivo performance and therapeutic effectiveness of the micelle-formulated drugs (Torchilin, 2007). These
studies serve as guidelines for the optimization of polymeric micelles for clinical applications. In order to design an effective micellar drug delivery system, several key physico-chemical properties of the micelles should be considered as a means to optimize performance. These include micelle size and size distribution, morphology, and stability (Nishiyama and Kataoka, 2006; Torchilin, 2007). In the past two decades, four polymeric micelle formulations loaded with chemotherapeutic drugs (NK911, SP1049C, Genexol-PM, and NK105) have entered clinical trial development (Matsumura et al., 2004; Danson et al., 2004; Kim et al., 2004). The results from the clinical studies have indicated that the polymeric micelle formulations reduce the toxicity associated with conventional formulations of these drugs that, in turn, results in a higher therapeutic index (Rapoport et al., 2003; Hamaguchi et al., 2005).
Figure 1.12: Schematic illustration of a polymeric micelle encapsulating drugs in its hydrophobic core.
Table 1.3: Polymeric micelle formulation of anticancer drugs currently in clinical trials.
Trade
Name Drug Polymer
Used Indication Phase Company
SP1049C Doxorubicin Poloxamer
Metastatic Adenocarcinom
a of the Upper Gastrointestinal
Tract
Phase III
Supratek Pharma Ltd.
Canada
NK911 Doxorubicin PEG –b–
poly(aspartic acid)
Metastatic or Recurrent Solid
Tumors
Phase II
Nippon Kayaku Co. Ltd., Japan Genexol-
PM Paclitaxel
Methoxy poly(ethylene glycol)-b-poly (lactide)
Lung and Brest Cancer
Phase II
Samyang Co., South Korea NK105 Paclitaxel
Modified PEG –b– poly(aspartic acid)
Stomach Cancer Phase II
NanoCarri er Co.
Ltd., Japan