» DRUG DELIVERY
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poly-ε-caprolactone nanoparticles for the treatment of intraocular hypertension is another example [5].
Passive Targeting
Passive accumulation of drug through leaky vasculature of a diseased area has been explored by many researchers as a potential for drug targeting. It was found that under certain pathological states, such as tumors, infarcts, and inflammation, permeability of vascular endothelial increases and they become leaky. In such areas with increased vascular permeability, nanoparticles such as micelles and liposomes can accumulate and exert their therapeutic effect. This spontaneous or ‘passive’ drug delivery is also known as an ‘enhanced permeability and retention’ (EPR) effect and is largely used for cancer targeting [6]. A marketed drug formulation, Doxil, which is doxorubicin incorporated into long circulating polyethylene glycol(PEG) coated liposomes, is an excellent example of EPR-based targeting [7].
Physical Targeting
Physical factors such as pH, or temperature have been explored for targeted drug delivery. The drug targeting is based on the fact that certain pathological areas differ from normal tissues in their pH and temperature. Various other physical attributes that can be used for physical targeting are Redox-sensitive systems, Magnetic-sensitive systems and Ultrasound-sensitive systems. In physical targeting, the carrier is distributed in systemic circulation and will not accumulate at the target site. However, the carrier will degrade in the target site, where the drug will release and accumulate [8]. All of these systems are discussed in detail below.
pH-sensitive Systems
The pH stimuli sensitive systems are the most studied systems. The pH of the pathological tissue is lower than the normal tissue, e.g. at the site of inflammation pH drops from 7.4 to pH 6.5. The same is observed in the case of infarcts [9]. Also, the pH is lower in the tumor mass (pH 6.5) than the surrounding tissue (pH 7.4). The microenvironment of a tumor is acidic because insufficient oxygen in tumors leads to hypoxia and causes production of lactic acid. This behavior is utilized for the preparation of pH-responsive drug or gene delivery systems, which can exploit the biochemical properties at the diseased site for targeted delivery [10, 11].
Various nanocarriers use the approach of pH difference to target the drug at a tumor site. Anticancer drugs can be conjugated to pH- sensitive polymers. This is done by conjugating the acid sensitive spacers between the drug and polymer, enabling the release of the drug either in relatively acidic extracellular fluids, or after endocytosis in endosomes or lysosomes of tumor cells [8].
Kamada et al. synthesized a pH-sensitive polymeric carrier, in which a poly(vinylpyrrolidone-co-dimethyl maleic anhydride) (PVD) was conjugated to doxorubicin (DOX), that gradually releases the free
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drug in response to changes in pH at the tumor site. They reported enhanced accumulation of doxorubicin at tumor site [12]
Another group illustrated the use of novel pH sensitive polymers, poly (beta amino ester) (PbAE) which is soluble below pH 6.5, to localize the release of paclitaxal in the acidic cellular environment of tumors. A nanoparticle formulation consisting of PEO-PbAE nanoparticles encapsulating paclitaxel was evaluated in vitro and in vivo. Results showed an increased level of paclitaxel intracellular (ovarian cancer cell) and intra-tumor compared to administration of the drug in solution, an increased cytotoxicity of paclitaxel as demonstrated by a higher percentage of cell death in vitro, and decreased tumor volume in vivo relative to paclitaxel solution. [13, 14]
Uses of nanocarriers such as liposomes and polymeric micelles have also been described that include the components with acid-labile bonds [15]. Long circulating PEGylated pH sensitive liposomes were prepared by Roux et al. using the combination of PEG and pH-sensitive terminally alkylated copolymer of N-isopropylacrylamide and methacrylic on the same liposome. pH-sensitive liposome attached with target specific ligands (folate and Tf) for cytosolic delivery has also been developed [16].
Temperature-sensitive Systems
Temperature-sensitive nanocarrier targeting is based on the fact that many pathological conditions demonstrate distinct hyperthermia. This area of research was also pushed forward due to various external means such as the magnetic field available to heat the targeted area of the body.
Meyer et al. showed the viability of the temperature-sensitive approach by demonstrating a significantly greater accumulation of the intravenously administered liposomes and other nanocarriers in the tumor upon heating to 42°C in human ovarian carcinoma xenograft model [17, 18]. Temperature-sensitive polymeric micelles can be prepared by using thermosensitive polymers which displays a lower critical solution temperature (LCST) in aqueous solution. LCST is the temperature below which the polymers are water soluble and above which they become water-insoluble. An example of thermosensitive polymers includes Poly(N-alkylacrylamide)s Poly(NIPAM) and its block copolymers, Poly(methyl vinyl ether) (PMVE) etc. [19].
Nakayama et al. developed thermosensitive micelles composed of Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) block copolymer as a thermo-responsive block, while biodegradable poly(d,l- lactide), poly(ε-caprolactone), or poly(d,l-lactide-co-ε-caprolactone) was used as a hydrophobic block. It was shown that doxorubicin exhibited rapid and thermo-responsive drug release while possessing a biodegradable character from these micelles [20].
For thermosensitive liposomal preparations, dipalmitoylphospha- tidylcholine (DPPC) can be used as a primary lipid. These DPPC liposomes become leaky to small water soluble molecules at a gel- to-liquid crystalline phase transition at the clinically achievable temperature of 41°C [8].
Liposomes can also be made temperature-sensitive via the incorporation of polymers which display a lower critical solution
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