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Subject Item: n2:20424894
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Subject Item: _:vb7596336
rdf:type: n3:Section
dc:title: liposomal drug delivery
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Subject Item: _:vb7596337
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rdf:value: long-circulating liposomes, which renders the carrier and thus its drug contents with a long blood-residence time. These favorable circulation properties result in an enhanced accumulation of liposomal drugs in the tumor area (Fig. 1A) (>>1<<). Tumor sites are characterized by an immature leaky vasculature due to angiogenesis.
n4:mentions: n2:17630918

Subject Item: _:vb7596338
rdf:type: n4:Context
rdf:value: However, the increased vascular permeability of tumor vasculature varies strongly between different tumor types and even within a tumor as was demonstrated in animal tumor models (>>2<<,3) as well as in cancer patients (4).
n4:mentions: n2:2459969

Subject Item: _:vb7596339
rdf:type: n4:Context
rdf:value: However, the increased vascular permeability of tumor vasculature varies strongly between different tumor types and even within a tumor as was demonstrated in animal tumor models (2,>>3<<) as well as in cancer patients (4).
n4:mentions: n2:17909055

Subject Item: _:vb7596340
rdf:type: n4:Context
rdf:value: However, the increased vascular permeability of tumor vasculature varies strongly between different tumor types and even within a tumor as was demonstrated in animal tumor models (2,3) as well as in cancer patients (>>4<<). Fig.
n4:mentions: n2:11234875

Subject Item: _:vb7596341
rdf:type: n4:Context
rdf:value: Liposomal formulations of doxorubicin and daunorubicin are either approved or under clinical investigation for treatment of several types of cancer (>>5<<), e.g. Kaposi’s Sarcoma, ovarian cancer, metastatic breast cancer, and multiple myeloma.
n4:mentions: n2:15717738

Subject Item: _:vb7596342
rdf:type: n4:Context
rdf:value: a significant level of uptake of liposomal doxorubicin by tumor cells followed by slow intracellular release, which ultimately renders the doxorubicin bioavailable as evidenced by its nuclear localization 2–3 days after administration (>>3<<). Laghina et al. quantified bioavailability of liposomal doxorubicin to be around 30 to 50% over several days after administration by measuring total tumor drug levels in comparison to the actual bioavailable drug levels measured in tumor
n4:mentions: n2:17909055

Subject Item: _:vb7596343
rdf:type: n4:Context
rdf:value: quantified bioavailability of liposomal doxorubicin to be around 30 to 50% over several days after administration by measuring total tumor drug levels in comparison to the actual bioavailable drug levels measured in tumor cell nuclei (>>6<<).
n4:mentions: n2:16203786

Subject Item: _:vb7596344
rdf:type: n3:Section
dc:title: hyperthermia
n3:contains: _:vb7596345 _:vb7596346

Subject Item: _:vb7596345
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rdf:value: Firm clinical proof of increased efficacy upon combining hyperthermia with chemotherapy has been obtained in the past 10 years from a randomized trial in bladder cancer (>>7<<), a trial in cervical cancer (8) and, more recently, a large randomized EORTC trial in high-grade soft tissue sarcomas.
n4:mentions: n2:14581436

Subject Item: _:vb7596346
rdf:type: n4:Context
rdf:value: Firm clinical proof of increased efficacy upon combining hyperthermia with chemotherapy has been obtained in the past 10 years from a randomized trial in bladder cancer (7), a trial in cervical cancer (>>8<<) and, more recently, a large randomized EORTC trial in high-grade soft tissue sarcomas.
n4:mentions: n2:17701535

Subject Item: _:vb7596347
rdf:type: n3:Section
dc:title: hyperthermia to improve liposomal chemotherapy
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Subject Item: _:vb7596348
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rdf:value: In analogy to the successful combination of vasoactive compounds such as tumor necrosis factor alpha and liposomal chemotherapy to increase tumor drug levels and anti tumor activity (>>3<<,10), hyperthermia can induce similar effects.
n4:mentions: n2:17909055

Subject Item: _:vb7596349
rdf:type: n4:Context
rdf:value: In analogy to the successful combination of vasoactive compounds such as tumor necrosis factor alpha and liposomal chemotherapy to increase tumor drug levels and anti tumor activity (3,>>10<<), hyperthermia can induce similar effects.
n4:mentions: n2:10956394

Subject Item: _:vb7596350
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rdf:value: 1B, can be anticipated and have already been demonstrated in some animal tumor models (>>11<<). The application of heat to tumors in animals in principle can involve similar technology as in humans, but is usually applied in a more straightforward way, for instance by submersing s.c. tumor-bearing extremities in a heating bath
n4:mentions: n2:11306483

Subject Item: _:vb7596351
rdf:type: n4:Context
rdf:value: tumor-bearing extremities in a heating bath (>>12<<). Intravital microscopic imaging is a tool often used to visualize intratumoral fate of thermosensitive liposomes and release of their content.
n4:mentions: n2:10728674

Subject Item: _:vb7596352
rdf:type: n4:Context
rdf:value: For this approach, heating of tissues placed in a dorsal skin-fold window chamber with implanted tumors can be achieved by placing it in a heated incubator (>>13<<), by using conductive heating for the whole (metal) window chamber (14), or, more precisely, by using a circular conductive heating ring designed for the window chamber (15).
n4:mentions: n2:10969790

Subject Item: _:vb7596353
rdf:type: n4:Context
rdf:value: For this approach, heating of tissues placed in a dorsal skin-fold window chamber with implanted tumors can be achieved by placing it in a heated incubator (13), by using conductive heating for the whole (metal) window chamber (>>14<<), or, more precisely, by using a circular conductive heating ring designed for the window chamber (15).
n4:mentions: n2:15041738

Subject Item: _:vb7596354
rdf:type: n4:Context
rdf:value: tumors can be achieved by placing it in a heated incubator (13), by using conductive heating for the whole (metal) window chamber (14), or, more precisely, by using a circular conductive heating ring designed for the window chamber (>>15<<).
n4:mentions: n2:20074595

Subject Item: _:vb7596355
rdf:type: n3:Section
dc:title: thermosensitive liposomes
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Subject Item: _:vb7596356
rdf:type: n4:Context
rdf:value: The formulation of such liposomes is based on pioneering work of Yatvin and Weinstein in the late 1970s (>>16<<), who described the use of liposomes composed of phospholipids that undergo a gel-to-liquid crystalline phase transition at temperatures of around 44°C, a process which, in the absence of cholesterol in the membrane, causes significant
n4:mentions: n2:364652

Subject Item: _:vb7596357
rdf:type: n4:Context
rdf:value: From this basic formulation, thermosensitive liposomes have been further developed, for instance, by providing them with long-circulating properties using poly(ethylene glycol) (>>12<<,15,17) or oligoglycerol-moieties (14) and by incorporating additional lipid compounds that further enhance membrane permeability at the phase transition temperature of the lipid membrane, e.g. lysolipid (12) or oligoglycerol-PG (14).
n4:mentions: n2:10728674

Subject Item: _:vb7596358
rdf:type: n4:Context
rdf:value: From this basic formulation, thermosensitive liposomes have been further developed, for instance, by providing them with long-circulating properties using poly(ethylene glycol) (12,>>15<<,17) or oligoglycerol-moieties (14) and by incorporating additional lipid compounds that further enhance membrane permeability at the phase transition temperature of the lipid membrane, e.g. lysolipid (12) or oligoglycerol-PG (14).
n4:mentions: n2:20074595

Subject Item: _:vb7596359
rdf:type: n4:Context
rdf:value: From this basic formulation, thermosensitive liposomes have been further developed, for instance, by providing them with long-circulating properties using poly(ethylene glycol) (12,15,>>17<<) or oligoglycerol-moieties (14) and by incorporating additional lipid compounds that further enhance membrane permeability at the phase transition temperature of the lipid membrane, e.g. lysolipid (12) or oligoglycerol-PG (14).
n4:mentions: n2:7971721

Subject Item: _:vb7596360
rdf:type: n4:Context
rdf:value: From this basic formulation, thermosensitive liposomes have been further developed, for instance, by providing them with long-circulating properties using poly(ethylene glycol) (12,15,17) or oligoglycerol-moieties (>>14<<) and by incorporating additional lipid compounds that further enhance membrane permeability at the phase transition temperature of the lipid membrane, e.g. lysolipid (12) or oligoglycerol-PG (14).
n4:mentions: n2:15041738

Subject Item: _:vb7596361
rdf:type: n4:Context
rdf:value: using poly(ethylene glycol) (12,15,17) or oligoglycerol-moieties (14) and by incorporating additional lipid compounds that further enhance membrane permeability at the phase transition temperature of the lipid membrane, e.g. lysolipid (>>12<<) or oligoglycerol-PG (14).
n4:mentions: n2:10728674

Subject Item: _:vb7596362
rdf:type: n4:Context
rdf:value: (12,15,17) or oligoglycerol-moieties (14) and by incorporating additional lipid compounds that further enhance membrane permeability at the phase transition temperature of the lipid membrane, e.g. lysolipid (12) or oligoglycerol-PG (>>14<<).
n4:mentions: n2:15041738

Subject Item: _:vb7596363
rdf:type: n3:Section
dc:title: intravascular and interstitial drug release approaches
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Subject Item: _:vb7596364
rdf:type: n4:Context
rdf:value: The released drug, currently doxorubicin, has been shown to be delivered efficiently from the tumor vasculature to the tumor cells as well as to vascular endothelial cells (>>18<<). More studies need to be done in order to establish the efficiency of this delivery process and whether this holds true for other chemotherapeutic drugs as well.
n4:mentions: n2:15486198

Subject Item: _:vb7596365
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rdf:value: Kong et al. showed increasing levels of extravascular appearance of liposomes with increasing temperatures from 39 to 42°C applied for 60 min to a human ovarian carcinoma xenograft tumor in mice (>>11<<). They also demonstrated that the increased vascular permeability in this tumor model lasted up to 4 h after treatment. Upon reaching optimal liposome accumulation levels in the tumor, a second hyperthermia treatment can be applied to
n4:mentions: n2:11306483

Subject Item: _:vb7596366
rdf:type: n4:Context
rdf:value: Since drug release from thermosensitive liposomes can occur very fast, with burst release of up to 70% of content in several minutes to maximal release within 1 h of hyperthermia (>>12<<,14,15), the duration of the second heat trigger can be tailored accordingly.
n4:mentions: n2:10728674

Subject Item: _:vb7596367
rdf:type: n4:Context
rdf:value: Since drug release from thermosensitive liposomes can occur very fast, with burst release of up to 70% of content in several minutes to maximal release within 1 h of hyperthermia (12,>>14<<,15), the duration of the second heat trigger can be tailored accordingly.
n4:mentions: n2:15041738

Subject Item: _:vb7596368
rdf:type: n4:Context
rdf:value: Since drug release from thermosensitive liposomes can occur very fast, with burst release of up to 70% of content in several minutes to maximal release within 1 h of hyperthermia (12,14,>>15<<), the duration of the second heat trigger can be tailored accordingly.
n4:mentions: n2:20074595

Subject Item: _:vb7596369
rdf:type: n3:Section
dc:title: imaging-guided drug delivery
n3:contains: _:vb7596370 _:vb7596371 _:vb7596372

Subject Item: _:vb7596370
rdf:type: n4:Context
rdf:value: Therefore, major efforts are being undertaken to provide liposomes with contrast agents to monitor tumor accumulation levels and drug release (>>1<<). Regarding thermosensitive liposomes, radionuclides and nuclear imaging can be used to image tumor accumulation of liposomes, but not drug release. Magnetic resonance imaging (MRI) to this respect has the advantage of being able to
n4:mentions: n2:17630918

Subject Item: _:vb7596371
rdf:type: n4:Context
rdf:value: Magnetic resonance imaging (MRI) to this respect has the advantage of being able to detect both liposome accumulation and drug release when a co-encapsulated MRI contrast agent is released together with the drug (>>19<<,20). In addition, MRI thermometry information on tumor temperatures during hyperthermia is available online. Imaging-guided drug delivery using thermosensitive liposomal nanocarriers will ultimately help to further optimize and
n4:mentions: n2:17202113

Subject Item: _:vb7596372
rdf:type: n4:Context
rdf:value: Magnetic resonance imaging (MRI) to this respect has the advantage of being able to detect both liposome accumulation and drug release when a co-encapsulated MRI contrast agent is released together with the drug (19,>>20<<). In addition, MRI thermometry information on tumor temperatures during hyperthermia is available online. Imaging-guided drug delivery using thermosensitive liposomal nanocarriers will ultimately help to further optimize and personalize
n4:mentions: n2:19002060

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