Asian Journal of Pharmacodynamics and Pharmacokinetics

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Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49 the tumor, cross vessel walls into the interstitium and penetrate multiple layers of solid tumor cells. Recent studies have demonstrated that poor penetration and limited distribution of doxorubicin in solid tumors are the main causes of its inadequacy as a chemotherapeutic agent. Encapsulation of doxorubicin into PEG-PE micelles increased its accumulation and penetration in tumors in terms of both the percentage of cells that were reached by the drug and the intracellular levels that were attained. This increased accumulation and penetration can be attributed to the efficient internalization of the drug-containing micelles by the endocytotic cell uptake mechanism and enhanced permeability and retention of tumors with leaky vasculature. High intracellular retention is especially important because doxorubicin must be internalized to be effective in tumor therapy. The doxorubicin- containing PEG-PE micelles had greatly increased antitumor activity in both subcutaneous and lung metastatic LLC tumor models compared with free doxorubicin. However, mice treated micelle- encapsulated doxorubicin showed fewer signs of toxicity than those treated with free doxorubicin. This drug packaging technology may provide a new strategy for design of cancer therapies. [29,30] At our laboratory, studied nanoparticle of doxorubicin eliminate the accumulation in tissues of tumor-bearing mice. Compared with general doxorubicin preparation, which is a marketed product, nanoparticle micelle of doxorubicin has the similar pharmacokinetics in the tissue, and the similar concentrations in the tumor tissue. Howerever, the accumulation of doxorubicin in the heart, spleen, kidney, lung, tumor, muscle and skin decreased significantly after three intravenous injections, showing that the nano-micelle can accumulatew the elimilation of doxorubicin in most tissues. It is deduced that the study was effects of doxorubicin after clinical use may be reduced significantly. [31] Pegylated liposomal doxorubicin is effective and well tolerated in relapsed ovarian cancer. When compared with topotecan in a phase III randomized trial, pegylated liposomal doxorubicin showed several advantages: improved quality of life, fewer severe adverse events, fewer dose modifications, less hematologic support, and lower total cost per patient. In platinum-sensitive patients, pegylated liposomal doxorubicin also produced a survival advantage. Results from prospective and retrospective studies further demonstrate the improved cardiac safety of pegylated liposomal doxorubicin compared to conventional anthracyclines. Based on survival and toxicity advantages and a once-monthly administration schedule, pegylated liposomal doxorubicin is the first-choice nonplatinum agent for relapsed ovarian cancer. Pegylated liposomal doxorubicin may also have clinical application in combination regimens for platinum-sensitive ovarian cancer, as consolidation/maintenance therapy for ovarian cancer, as a component of first-line therapy for ovarian cancer, and in the treatment of other gynecologic malignancies. Future clinical trials will further define and maximize the role of pegylated liposomal doxorubicin in the treatment of ovarian cancer and other gynecologic malignancies. [32] Doxorubicin nanoparticles A novel hyaluronic acid-poly(ethylene glycol)-poly(lactide-co-glycolide) (HA-PEG-PLGA) copolymer was synthesized and characterized by infrared and nuclear magnetic resonance spectroscopy. The nanoparticles of doxorubicin (DOX)-loaded HA-PEG-PLGA were prepared and compared with monomethoxy (polyethylene glycol) (MPEG)-PLGA nanoparticles. Nanoparticles were prepared using drug-to-polymer ratios of 1:1 to 1:3. Drug-to-polymer ratio of 1:1 is considered the optimum formulation on the basis of low particle size and high entrapment efficiency. The optimized nanoparticles were characterized for morphology, particle size measurements, differential scanning calorimetry, x-ray diffractometer measu- rement, drug content, hemolytic toxicity, subacute toxicity, and in vitro DOX release. The in vitro DOX release study was performed at pH 7.4 using a dialysis membrane. HA-PEG-PLGA nanoparticles were able to sustain the release for up to 15 days. The tissue distribution studies were performed with DOX-loaded HA-PEG-PLGA and MPEG-PLGA nanoparticles after intravenous (IV) injection in Ehrlich ascites tumor–bearing mice. The tissue distribution studies showed a higher concentration of DOX in the tumor as compared with 39
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49 MPEG-PLGA nanoparticles. The in vivo tumor inhibition study was also performed after IV injection of DOX-loaded HA-PEG-PLGA nanoparticles up to 15 days. DOX-loaded HA-PEG-PLGA nanoparticles were able to deliver a higher amount of DOX as compared with MPEG-PLGA nanoparticles. The DOX-loaded HA-PEG-PLGA nanoparticles reduced tumor volume significantly as compared with MPEG-PLGA nanoparticles. [33] Chitosan, PCEP (poly{[(cholesteryl oxocarbonylamido ethyl) methyl bis(ethylene) ammonium iodide] ethyl phosphate}), and magnetic nanoparticles (MNPs) were evaluated for the safe delivery of genes in the eye. Prow et al studied ocular nanoparticle toxicity and transfection of the retina and retinal pigment epithelium. Rabbits were injected with nanoparticles either intravitreally (IV) or subretinally (SR) and sacrificed 7 days later. Eyes were grossly evaluated for retinal pigment epithelium abnormalities, retinal degeneration, and inflammation. All eyes were cryopreserved and sectioned for analysis of toxicity and expression of either enhanced green or red fluorescent proteins. All of the nanoparticles were able to transfect cells in vitro and in vivo. IV chitosan showed inflammation in 12/13 eyes, whereas IV PCEP and IV MNPs were not inflammatory and did not induce retinal pathology. SR PCEP was nontoxic in the majority of cases but yielded poor transfection, whereas SR MNPs were nontoxic and yielded good transfection. Therefore, researchers concluded that the best nanoparticle evaluated in vivo was the least toxic nanoparticle tested, the MNP. [34] Liposomes targeted by fusion phage proteins Targeting of nanocarriers has long been sought after to improve the therapeutic indices of anticancer drugs. Jayanna et al provide the proof of principle for a novel approach of nanocarrier targeting through their fusion with target-specific phage coat proteins. The source of the targeted phage coat proteins are landscape phage libraries—collections of recombinant filamentous phages with foreign random peptides fused to all 4000 copies of the major coat protein. Prashanth et al exploit in our approach the intrinsic physicochemical properties of the phage major coat protein as a typical membrane protein. Landscape phage peptides specific for specific tumors can be obtained by affinity selection, and purified fusion coat proteins can be assimilated into liposomes to obtain specific drug-loaded nanocarriers. As a paradigm for inceptive experiments, a streptavidin-specific phage peptide selected from a landscape phage library was incorporated into 100-nm liposomes. Targeting of liposomes was proved by their specific binding to streptavidincoated beads. [35] Drug Loading and Release From Biodegradable Microcapsules Microcapsules made of biopolymers are of both scientific and technological interest and have many potential applications in medicine, including their use as controlled drug delivery devices. The present study makes use of the electrostatic interaction between polycations and polyanions to form a multilayered microcapsule shell and also to control the loading and release of charged drug molecules inside the microcapsule. Micron-sized calcium carbonate (CaCO 3 ) particles were synthesized and integrated with chondroitin sulfate (CS) through a reaction between sodium carbonate and calcium nitrate tetrahydrate solutions suspended with CS macromolecules. Oppositely charged biopolymers were alternately deposited onto the synthesized particles using electrostatic layer-by-layer self-assembly, and glutaraldehyde was introduced to cross-link the multilayered shell structure. Microcapsules integrated with CS inside the multilayered shells were obtained after decomposition of the CaCO 3 templates. The integration of a matrix (i.e., CS) permitted the subsequent selective control of drug loading and release. The CS-integrated microcapsules were loaded with a model drug, bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA), and it was shown that pH was an effective means of controlling the loading and release of FITC-BSA. Such CS-integrated microcapsules may be used for controlled localized drug delivery as biodegradable devices, which have advantages in reducing systemic side effects and increasing drug efficacy. [36] 40
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