Cancer Therapy with Nanotechnology-Based Drug Delivery Systems: Applications and Challenges of Liposome Technologies for Advanced Cancer Therapy
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Nanotechnologies have the potential to improve cancer therapy. In particular, liposomes and micelles serve as nano-sized drug delivery carriers for the administration of cancer drugs. Although micelles have not been approved by the Food and Drug Administration (FDA) in USA, some liposomal drugs have been already approved for use in anticancer therapy. In most cases, these liposomal drugs have improved pharmacokinetics and reduced side effects due to the encapsulation of the drug. Also, passive targeting to the tumor can be achieved due to physiological properties that lead to the enhanced permeability and retention (EPR) effect in tumor tissue. More recently, modification of the liposomal surface with active targeting molecules such as antibodies or natural receptor ligands has been investigated in clinical trials. Moreover, novel strategies for drug release, activation, and delivery with physical stimuli have been developed. There is a plethora of preclinical and clinical data about liposomal drugs for cancer therapy because they have been utilized as commercially available drugs for a long time. In the present review, we summarize the use of tumor-targeting technologies and approved liposomal antitumor drugs, describe their properties, and assess applications and challenges of liposome technologies for advanced cancer therapy.Keywords:
Cancer Therapy
Various kinds of long-circulating liposome, such as ganglioside GM1-, polyethyleneglycol- (PEG-), and glucuronide-modified liposomes, have been developed for passive targeting of liposomal drugs to tumours. To evaluate the in vivo behaviour of such long-circulating liposomes, we investigated the liposomal trafficking, especially early trafficking just after injection of liposomes, by a non-invasive method using positron emission tomography (PET). Liposomes composed of dipalmitoylphosphatidylcholine, cholesterol, and modifier, namely, GM1, distearoylphosphatidylethanolamine (DSPE)–PEG or palmityl-D-glucuronide (PGlcUA), were labelled with [2-18F]-2-fluoro-2-deoxy-D-glucose ([2-18F]FDG), and administered to mice bearing Meth A sarcoma after having been sized to 100 nm. A PET scan was started immediately after injection of liposomes and continued for 120 min. PET images and time–activity curves indicated that PEG liposomes and PGlcUA liposomes were efficiently accumulated in tumour tissues time dependently from immediately after injection. In contrast, GM1 liposomes accumulated less in the tumour as was also the case for control liposomes that contained dipalmitoylphosphatidylglycerol (DPPG) instead of a modifier. Long-circulating liposomes including GM1 liposomes, however, remained in the blood circulation and avoided liver trapping compared with control DPPG liposomes. These data suggest that PGlcUA and PEG liposomes start to accumulate in the tumour just after injection, whereas GM1 liposomes may accumulate in the tumour after a longer period of circulation.
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The liposome particle size is an important parameter because it strongly affects content release from liposomes as a result of different bilayer curvatures and lipid packing. Earlier, we developed pH-responsive polysaccharide-derivative-modified liposomes that induced content release from the liposomes under weakly acidic conditions. However, the liposome used in previous studies size was adjusted to 100-200 nm. The liposome size effects on their pH-responsive properties were unclear. For this study, we controlled the polysaccharide-derivative-modified liposome size by extrusion through polycarbonate membranes having different pore sizes. The obtained liposomes exhibited different average diameters, in which the diameters mostly corresponded to the pore sizes of polycarbonate membranes used for extrusion. The amounts of polysaccharide derivatives per lipid were identical irrespective of the liposome size. Introduction of cholesterol within the liposomal lipid components suppressed the size increase in these liposomes for at least three weeks. These liposomes were stable at neutral pH, whereas the content release from liposomes was induced at weakly acidic pH. Smaller liposomes exhibited highly acidic pH-responsive content release compared with those from large liposomes. However, liposomes with 50 mol% cholesterol were not able to induce content release even under acidic conditions. These results suggest that control of the liposome size and cholesterol content is important for preparing stable liposomes at physiological conditions and for preparing highly pH-responsive liposomes for drug delivery applications.
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The uptake mechanisms of liposomes by rat peritoneal macrophages (PMs) were investigated. Incubation of liposomes with fresh rat serum enhanced the uptake of liposomes depending on the liposome size and cholesterol (CH) content. The binding of liposomes was also enhanced by serum, and this increase depended on the size and CH content as in the case of liposome uptake, which suggested that the binding of opsonized liposomes with PMs govern the extent in liposome uptake. The rate constant for the internalization (kint) was calculated by measuring both uptake and binding. The kint cannot explain the variation of liposome uptake for different sizes and CH contents. The kint values for liposomes with high (44%) and medium (33%) CH contents were constant (2.5-1), while those for liposomes with low (22%) Ch content were significantly elevated (5-9h-1). These results indicate the persence of at least two kinds of uptake mechanisms of liposomes. Treatment of serum with anti-C3 antiobdy completly inhibited the enhanced uptake of CH-high, large liposomes, which suggested that complement receptor-mediated phagocytosis may be an uptake mechanism for CH-high and -medium liposomes. In addition, complement-independent enhanced uptake was suggested for CH-low liposomes, since no inhibition was observed for CH-low liposomes by anti-C3 antibody and these liposomes were disintegrated in serum via complement-independent pathway. These results provided evidence that PMs take up liposomes via complement-dependent and indepenedent mechanisms depending on the CH content of the liposomes.
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Our research aims to answer the following questions. Can cancer progression be stopped by changing the body condition of person with cancer? Can cancer be cured?If cancer progression can be stopped, what is the underlying mechanism?Almost 70 years ago, Goldblatt H. & Cameron G. reported on the idea of alkalization therapy. Before that, Otto Warburg had been studying the metabolism of cancer and had discovered the essential nature of cancer. He published a review in Science in 1956 under the title "On the origin of cancer cells". From his phenomena described above, we established the theoretical rationale for alkalization therapy, based on the question of "How does cancer form and what is its nature"?In this paper, we describe a method to reconstruct the limitations and weaknesses of modern cancer medicine as Science-based Medicine using an inductive method, and to present a new vision of cancer therapy. How should we treat cancer? (Case presentation): Using a specific clinical case, we present patients in whom were successfully treated with no or few anticancer drugs.The biggest weakness of current cancer treatments is that they only treat the cancer and not the actual patient. The "alkalization therapy" that we advocate does not compete with any of the current standard treatments, but improves the effectiveness of standard treatments, reduces side effects, and lowers medical costs.
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In order to reveal quantitatively interaction of complement (C) system with liposomes, we determined C3 fragments associated with the liposomes having different sizes after incubation in human plasma. The amount of C3 fragments per unit surface area on the unstable liposomes (Man-liposomes) which modified with synthesized glycolipid (cetylmannoside, Man) increased with the increase in the liposome size, whereas that of C3 fragments on the stable ones (PC-liposomes) was little found. In addition, the instability of Man-liposomes also increased with the increase in the liposome size and there was linear correlation. On the other hand, the amount of bound plasma proteins per unit surface area of liposomes was approximately constant regardless of differences of lipid composition and size, and showed no correlation with instability of the liposomes in the plasma. These in vitro results indicate that the instability of Man-liposomes is governed by the affinity of C system and the C system can recognize not only liposome surface characteristics but also liposome sizes. To demonstrate clearly the reason for the linear correlation between the affinity of C system and liposome size, we discussed the underlying mechanism based on the previous finding that the activation of C system by Man-MLVs was enhanced through classical C pathway and presented the hypothesized osculating model on the assumption that extent of C activation is governed by attachment of a C activator.
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