3.MICRO AND NANO DRUG DELIVERY SYSTEMS(cont.)

3.MICRO AND NANO DRUG DELIVERY SYSTEMS(cont.)
3.1.Micelles

Micelles are ideal bioactive nanocarriers, especially for water insoluble agents. Many amphiphilic block copolymers can be used for this purpose. Polymers can self-associate to form spherical micelles in aqueous solution by keeping hydrophilic ends as the outer shell and the hydrophobic ends as the core. Hydrophobic drugs can be entrapped in the core during micelle formation process. Polymeric micelles have good thermodynamic stability in
physiological solutions, as indicated by their low critical micellar concentration, which makes them stable and prevents their rapid dissociation in vivo. The sizes of micelles are generally less than 100 nm in diameter. This provides them with long-term circulation in blood stream and enhanced endothelial cell ermeability in the vicinity of solid tumors by passive diffusion. If site-specific ligands or antibodies are conjugated to the surface of the micelles, the drug targeted delivery potential of polymeric micelles can be enhanced.Kataoka et al (2000) studied the effective targeting of cytotoxic agents to solid tumors by polymeric micelles. They conjugated doxorubicin to poly(ethylene glycol)-poly( , -aspartic acid) block copolymers and showed that these micelles achieved prolonged circulation in the blood compartment and accumulated more in
the solid tumor, leading to complete tumor regression against mouse C26 tumor. Rapoport (1999) studied stabilization and activation of Pluronic micelles for tumor- targeted drug delivery. Aliabadi et al (2005a) examined
the potential of polymeric micelles to modify the pharmacokinetics and tissue distribution of cyclosporine A (CsA). Their results demonstrated that PEO-b-PCL micelles can effectively solubilize CsA confining CsA to the blood circulation and restricting its access to tissues such as kidney, perhaps limiting the onset of toxicity. They also investigated micelles of methoxy poly (ethylene oxide)–b–poly ( –caprolactone) (PEO–b–PCL) as alternative vehicles for the solubilization and delivery of Cyclosporine A (Aliabadi et al 2005b). They concluded that these nanoscopic PEO–b–PCL micelles have high potential as drug carriers for efficient solubilization and controlled delivery of CsA. Prompruk et al (2005) synthesized a functionalized copolymer with three polymeric components,poly (ethylene glycol)–block–poly (aspartic acid–stat- phenylalanine) and investigated its potential to form micelles via ionic interactions with diminazene aceturate as a model water-soluble drug.Wasylewska et al (2004) entrapped human prostatic acid phosphatase (PAP)entrapped in AOT–isooctane–water reverse micelles and studied the kinetics of1–naphthyl phosphate and phenyl phosphate hydrolysis, catalyzed by PAP. Wang et al (2004) prepared polymeric micelles from poly (ethylene glycol)–distearoyl phosphoethanolamine conjugates (PEG–DSPE) loaded with
Vitamin K3 (VK3) and with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). These micelles were stable for 6 months during storage at 4°C and no change in their size or release of the incorporated drugs were observed. They showed that these loaded micelles resulted in synergistic anticancer effects against both murine and human cancer cells in vitro. Kang et al (2004) prepared A-B-A triblock and star-block amphiphilic copolymers such as poly (N–(2–hydroxypropyl) methacrylamide)–block–poly (D,L–lactide)–block–poly (N–(2–hydroxy propyl) methacrylamide), poly (N–vinyl-2–pyrrolidone)–block–poly (D,L–lactide)–block–poly (N–vinyl–2–pyrrolidone), star–poly (D,L–lactide)–block–poly
(N–(2–hydroxypropyl) methacryl amide) and star–poly (D,L–lactide)–block–poly (N–vinylpyrrolidone). They reported that all copolymers self-assembled in aqueous solution to form supramolecular aggregates of 20–180 nm in size. The prepared triblock copolymer micelles were examined as carriers for two drugs, indomethacin and paclitaxel, which are poorly water- soluble. Carrillo and Kane (2004) studied the formation and characterization of self– assembled nanoparticles of controlled sizes based on amphiphilic block copolymers synthesized by ring-opening metathesis polymerization. They showed that the monomer undergoes living polymerization and forms assembled nanoparticles of controlled size. The obtained micelles were fairly monodisperse with dimensions of 30–80 nm depending on the composition of the block polymer.Synthetic copolymers containing phosphorylcholine structure can also be used in the formation of micelles. Phosphorylcholine-based polymers mimic the surface of natural phospholipid membrane bilayers and therefore
demonstrate good biocom- patability. Salvage et al (2005) copolymerised 2-methacryloyloxyethyl phospho- rylcholine (MPC) with two pH responsive comonomers, 2–(diethylamino) ethyl methacrylate (DEA) and 2–
(diisopropyl amino) ethyl methacrylate (DPA), in order to develop pH responsive biocompatible drug delivery vehicles. Koo et al (2005) studied sterically stabilized micelles (SSM) and evaluated camptothecin- containing SSM CPT–SSM) as a new nanomedicine for parenteral administration where camptothecin is a well-established topoisomerase I inhibitor against a broad spectrum of cancers. Konno et al (2001) have shown that 2-ethacryloyloxyethyl phosphorylcholine (MPC) polymer immobilized on poly (l–lactic acid) nanopar- ticles effectively suppressed any unfavourable interactions with biocomponents and improved the blood compatibility of the nanoparticles. It has been suggested that the nanoparticles immobilized with the MPC polymer have the potential use as long–circulating micelles and are good candidates for carrying drugs and diagnostic reagents which can come in contact with blood components. Nishiyama et al (2005) published a review article about
construction and characteristic behaviors of intracellular environment-sensitive micelles that selectively exert drug activity and gene expression in live cells. Xiong et al (2005) grafted poly (lactic acid) to both ends of
Pluronic F87 block copolymer (PEO–PPO–PEO) to obtain amphiphilic P(LA-b-EO-b-PO-b-EO-b-LA) block copolymers. Various types of particles consisting of small micelles were obtained due to the complex structure of the copolymers and a constant initial release rates were observed for procain hydrochloride. Sot and coworkers (2005) investigated the behaviour of N–hexadecanoyl sphingosine (Cer16), N–hexanoylsphingosine (Cer6) and N–acetyl sphingosine (Cer2) ceramides in aqueous media and in lipid-water systems. Cer16 behaved as an insoluble non-swelling amphiphile while both Cer6 and Cer2 behaved as soluble amphiphiles in aqueous solutions. They observed micelle formations for Cer6 and Cer2 at high concentrations as well as phospholipid monolayer formation when the air-water interface is occupied by a phospholipid.Responsivity can be added to micelles by combining pH or temperature sensitive functional groups into the structures. Cammas et al (1997) prepared thermo- responsive polymeric micelles from amphiphilic block copolymers composed of N–isopropylacrylamide as a thermo-responsive outer shell and styrene as hydrophobic inner core. Leroux et al (2001) studied N–isopropylacrylamide bearing pH-responsive polymeric micelles and
liposomes as a delivery system for the photosensitizer aluminum chloride phthalocyanine (AlClPc), which was evaluated in photodynamic therapy. pH-responsive polymeric micelles loaded with AlClPc were found to exhibit
increased cytotoxicity against EMT-6 mouse mammary cells in vitro. Liu et al (2003) synthesized cholesteryl end-capped thermally responsive amphiphilic polymers with two different hydrophobic/hydrophilic chain-length
ratios from the hydroxyl-terminated random poly (N–isopropylacrylamide–co–N, N–dimethylacrylamide) and cholesteryl chloroformate. The micellar nanoparticles prepared from the amphiphilic polymers demonstrated
temperature sensitivity. It was suggested that these nanoparticles would make an interesting drug delivery system. Nostrum (2004) reviewed the results of photosensitizers for photodynamic therapy including drug
loading, biodistribution studies, and therapeutic efficiency and concluded that pH-sensitive micelles appeared to be promising candidates for photosensitizer delivery.

Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey