»
DRUG DELIVERY
»
temperature (LCST), slightly above the physiological temperature. Because these polymers are soluble below LCST and precipitate when the temperature increases above the LCST, they can damage the liposomal membrane during precipitation and allow for drug release. Poly(N-isopropylacrylamide) (NIPAM) can be used for such liposome preparations. For example, Han et al. investigated the release of doxorubicin from liposomes composed of poly(N- isopropylacrylamide-co-acrylamide) (NIPAAm-AAM) and PEG. The release of doxorubicin was increased around the transition temperature of the polymer. In addition, modified liposomes were found to be stable in the serum compared with unmodified liposomes suggesting that NIPAAm-AAM/PEG modified liposomes are suitable for targeted-drug delivery [21, 22].
Redox Potential Sensitive Systems
The use of high redox potential difference, which exists between the reducing intracellular space and oxidizing extracellular space, can also be utilized for the formulation of stimuli-sensitive systems. To make use of redox potential, the chemistry of the disulfide bond is employed. In these systems, the active molecule, drug or DNA, are loaded into nanocarriers whose structure is maintained by a disulfide bond. As soon as those bonds are reduced to thiol groups due to the presence of high glutathione inside the cells, the integrity of the carrier is compromised and the drug is released [23]. Cavallaro et al. have used polymers that are positively charged and thiol groups incorporated into the polymer structure to complex DNA (via positive charge) and to form polymeric network (via disulfide bridges formed from groups). When reduced, disulfide bridges convert back to thiols, polymeric carrier disintegrates and DNA release is facilitated [24]. Kirpotin et al. reported other redox-sensitive liposomes with long circulating property made up of detachable disulfide linked PEG polymer coating [25].
Magnetic-sensitive Systems
The concept of magnetic drug targeting was first introduced by Widder et al. in 1979. The concept is based upon conjugation of a drug molecule with magnetic particles and guiding these magnetic particles towards the intended pathology site under the influence of an external magnetic field [26].
In magnetic-sensitive systems, iron oxide nanoparticles, namely magnemite or magnetite, with particle size 4–10 nm are used. They are referred to as superparamagnetic iron oxide nanoparticles (SPIONs) based on their superparamagnetic properties and small size.
Gang et al. have demonstrated targeting of magnetic poly e-caprolactone nanoparticles loaded with gemcitabine in a pancreatic cancer xenograft mouse model using external magnets. Alexiou et al. have used mitoxantrone loaded SPION and targeted them to VX2 squamous cell carcinoma in rabbits by using external magnets [27].
Another interesting approach of SPIONs in tumor targeting is to increase the local temperatures by an alternating magnetic field. The method is based on tumor accumulation of SPION and the exposure
68 | | September/October 2013 - 15TH ANNIVERSARY ISSUE
of the tumor to an alternating magnetic field, whereby the tumor is eliminated by heat developed by oscillating SPION. The temperature increase achieved by this depends on the size, shape and accumulation of the nanoparticles in the intended site and on the applied alternating magnetic field [23].
Ultrasound-sensitive Systems
The concept of ultrasound-sensitive drug delivery systems is based upon accumulation of nanocarrier in the required area where they can be made leaky by the local application of an external ultrasound. Once the structure is disrupted, nanocarriers can liberate incorporated drugs or genes [23].
Polymeric micelles incorporated with doxorubicin have been prepared. They demonstrated the release after ultrasonication was applied [28]. A similar approach was used by Tiukinhoy-Laing et al. for the local release of thrombolytic enzymes, plasminogen activator, from echogenic liposomes in the area of clot formation. In this case, specific binding of plasminogen activator with fibrin additionally facilitated drug accumulation in the target zone providing a promising multifunctionality: contrast properties, targeting ability and thrombolytic drug release [29].
Active Targeting
Active targeting is a non-invasive approach, in which the drug is transported to the target organ or tissue using site-specific ligands. The pairing of drug carriers, such as liposome, particulate nanocarrier etc., with a ligand leads to the specific targeting to selected cells. Targeting ligands can be broadly classified as proteins (mainly antibodies and their fragments such as TAT), nucleic acids (aptamers), or other receptor ligands (peptides, vitamins, and carbohydrates) [2, 30].
One of the earliest approaches of active drug targeting is a direct coupling of a drug to a targeting moiety. Immunotoxins is an example of this approach [31]. In addition, particulate or reservoir type drug carriers can be used to load the drug which provides the advantage of high loading capacity, eliminated need for covalent conjugation of the drug, protection of the entrapped drug from enzymatic inactivation by formulation, along with the possibility to control size, permeability and plasmic longevity (PEGylated) [32].
Targeting cancer with a monoclonal antibody (mAb) was described by Milstein in 1983 [33]. Afterwards, the feasibility of using an antibody as a ligand for targeting has been demonstrated with many molecules. For example, mAb rituximab (Rituxan) was used for treatment of patients with non-Hodgkin’s lymphoma (a type of cancer that originates in lymphocytes), Trastuzumab (Herceptin), an anti-HER2 mAb that binds to ErbB2 receptors for the treatment of breast cancer, and many more [34].
Targeting tumors with folate-modified nanocarriers is another popular approach, since folate receptor (FR) expression is frequently overexpressed in many tumor cells. Liposomal daunorubicin is an
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122 |
Page 123 |
Page 124 |
Page 125 |
Page 126 |
Page 127 |
Page 128 |
Page 129 |
Page 130 |
Page 131 |
Page 132 |
Page 133 |
Page 134 |
Page 135 |
Page 136 |
Page 137 |
Page 138 |
Page 139 |
Page 140 |
Page 141 |
Page 142 |
Page 143 |
Page 144 |
Page 145 |
Page 146 |
Page 147 |
Page 148 |
Page 149 |
Page 150 |
Page 151 |
Page 152 |
Page 153 |
Page 154 |
Page 155 |
Page 156