_:b7596344 . _:b431810393 . _:b7596347 . . . _:b431810392 . _:b431810395 . _:b431810394 . . _:b7596336 "liposomal drug delivery" . _:b431810405 . _:b431810378 . _:b431810404 . . _:b7596369 . _:b431810407 . . _:b7596342 "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\u20133\u00A0days 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" . _:b431810354 . . _:b431810355 . _:b431810406 . . _:b431810401 . _:b431810356 . _:b431810357 . _:b431810395 . _:b431810358 . _:b431810359 . _:b431810401 . _:b431810360 . _:b431810361 . _:b431810362 . _:b431810363 . _:b431810400 . _:b431810364 . _:b431810365 . _:b431810366 . . . _:b7596355 . _:b431810403 . . _:b431810367 . . _:b431810402 . . _:b7596363 . _:b431810413 . _:b431810372 . _:b431810412 . _:b7596353 "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)." . _:b7596360 "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)." . _:b431810414 . . _:b431810354 . . _:b7596368 . _:b431810374 . _:b431810409 . . _:b431810408 . _:b7596363 "intravascular and interstitial drug release approaches" . _:b431810411 . _:b431810394 . _:b431810410 . _:b431810377 . _:b7596354 "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<<)." . . _:b7596358 "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)." . _:b7596361 "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)." . _:b7596350 "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" . _:b431810379 . . _:b431810385 . _:b431810361 . _:b7596364 . . _:b431810376 . _:b7596346 . _:b431810363 . _:b7596339 "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)." . . . . _:b431810405 . . _:b431810357 . _:b7596369 "imaging-guided drug delivery" . _:b7596359 "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)." . _:b7596351 . . _:b431810358 . _:b431810373 . _:b7596343 . _:b431810396 . . . "PMC0" . _:b7596357 . . _:b7596338 . _:b431810362 . _:b431810359 . _:b7596357 "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)." . _:b7596366 . _:b431810390 . _:b431810404 . . _:b431810402 . _:b431810365 . _:b431810371 . _:b431810412 . _:b431810386 . _:b7596361 . . _:b431810355 . _:b431810357 "4"^^ . _:b431810384 . _:b7596337 "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.\u00A01A) (>>1<<). Tumor sites are characterized by an immature leaky vasculature due to angiogenesis." . _:b431810356 "4"^^ . . _:b431810359 "3"^^ . _:b431810358 "3"^^ . _:b7596340 . . _:b431810354 "6"^^ . _:b7596341 . _:b431810388 . . _:b7596342 . . _:b7596343 . _:b431810355 "4"^^ . _:b7596345 . . _:b7596336 . _:b7596359 . _:b431810389 . _:b431810365 "3"^^ . _:b7596337 . . _:b431810364 "3"^^ . _:b7596338 . . _:b7596339 . _:b431810367 "3"^^ . _:b7596363 _:b7596364 . _:b431810414 . _:b7596363 _:b7596365 . _:b431810366 "3"^^ . _:b7596348 . _:b7596363 _:b7596366 . _:b7596363 _:b7596367 . _:b431810361 "3"^^ . _:b7596349 . _:b431810368 . _:b431810360 "3"^^ . _:b7596350 . _:b431810363 "3"^^ . _:b7596351 . . _:b7596343 "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<<)." . _:b431810362 "3"^^ . . _:b7596344 . _:b7596363 _:b7596368 . _:b431810373 "2"^^ . _:b7596345 . _:b431810360 . . . _:b431810372 "2"^^ . _:b7596346 . _:b7596355 _:b7596360 . _:b7596355 _:b7596361 . _:b431810375 "2"^^ . _:b7596355 _:b7596362 . _:b7596347 . _:b7596362 "(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<<)." . . _:b431810397 . . _:b431810374 "2"^^ . _:b431810392 . _:b7596356 . _:b7596351 "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." . _:b7596347 "hyperthermia to improve liposomal chemotherapy" . _:b7596372 "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" . _:b431810369 "2"^^ . _:b431810411 . _:b7596357 . _:b7596355 _:b7596356 . _:b7596355 _:b7596357 . _:b431810368 "2"^^ . _:b7596355 _:b7596358 . _:b7596358 . _:b431810383 . . _:b7596355 _:b7596359 . _:b7596341 "Liposomal formulations of doxorubicin and daunorubicin are either approved or under clinical investigation for treatment of several types of cancer (>>5<<), e.g. Kaposi\u2019s Sarcoma, ovarian cancer, metastatic breast cancer, and multiple myeloma." . _:b431810381 . _:b431810371 "2"^^ . . . _:b7596359 . _:b431810398 . . _:b431810370 "2"^^ . _:b7596364 "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." . _:b7596352 . _:b431810381 "2"^^ . _:b431810413 . _:b7596353 . . . _:b431810380 "2"^^ . _:b7596354 . _:b431810383 "2"^^ . _:b7596355 . _:b431810382 "2"^^ . _:b7596364 . . _:b431810377 "2"^^ . . _:b7596371 "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" . _:b7596365 . . _:b7596337 . _:b431810376 "2"^^ . _:b7596352 "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)." . . _:b7596362 . _:b7596366 . _:b431810403 . _:b431810379 "2"^^ . _:b431810407 . _:b7596367 . _:b431810378 "2"^^ . _:b7596360 . _:b7596365 "Kong et al. showed increasing levels of extravascular appearance of liposomes with increasing temperatures from 39 to 42\u00B0C applied for 60\u00A0min 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\u00A0h after treatment. Upon reaching optimal liposome accumulation levels in the tumor, a second hyperthermia treatment can be applied to" . _:b7596360 . . _:b431810389 "2"^^ . _:b7596361 . _:b431810388 "2"^^ . _:b7596362 . _:b431810391 "2"^^ . _:b7596367 . _:b7596363 . . _:b431810390 "2"^^ . _:b7596372 . _:b431810393 . _:b431810400 . _:b7596352 . _:b431810385 "2"^^ . . _:b7596370 "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" . . _:b7596348 "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." . _:b7596355 "thermosensitive liposomes" . _:b431810384 "2"^^ . _:b431810387 "2"^^ . _:b7596369 _:b7596370 . . _:b7596369 _:b7596371 . _:b7596369 _:b7596372 . . _:b431810386 "2"^^ . _:b7596345 "Firm clinical proof of increased efficacy upon combining hyperthermia with chemotherapy has been obtained in the past 10\u00A0years 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." . _:b431810357 . _:b7596368 . _:b431810356 . _:b431810397 "2"^^ . _:b431810356 . _:b7596353 . _:b431810382 . _:b7596369 . _:b431810396 "2"^^ . . . _:b7596370 . _:b431810359 . _:b431810399 . _:b431810399 "2"^^ . . _:b7596371 . _:b431810358 . _:b431810375 . _:b431810398 "2"^^ . _:b431810406 . _:b431810393 "2"^^ . _:b431810409 . _:b431810392 "2"^^ . _:b431810355 . _:b7596368 "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\u00A0h of hyperthermia (12,14,>>15<<), the duration of the second heat trigger can be tailored accordingly." . _:b7596336 _:b7596340 . _:b7596336 _:b7596341 . _:b431810380 . _:b431810395 "2"^^ . _:b7596336 _:b7596342 . _:b431810354 . . _:b7596336 _:b7596343 . _:b7596336 _:b7596337 . _:b431810394 "2"^^ . . _:b7596336 _:b7596338 . _:b431810365 . _:b7596336 _:b7596339 . _:b431810387 . _:b431810405 "2"^^ . _:b431810364 . _:b7596356 . _:b431810404 "2"^^ . _:b7596348 . _:b431810367 . _:b7596340 . _:b431810407 "2"^^ . _:b431810366 . _:b431810406 "2"^^ . _:b431810361 . . . . _:b431810401 "2"^^ . _:b431810360 . _:b431810400 "2"^^ . _:b431810363 . . . . . _:b431810403 "2"^^ . _:b431810362 . _:b431810370 . _:b7596347 _:b7596348 . _:b7596347 _:b7596349 . _:b7596342 . _:b431810402 "2"^^ . _:b431810373 . _:b7596347 _:b7596350 . . _:b7596347 _:b7596351 . _:b7596338 "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)." . _:b431810391 . . _:b431810413 "2"^^ . _:b431810372 . . _:b7596344 _:b7596345 . _:b431810412 "2"^^ . _:b431810375 . _:b7596344 _:b7596346 . . _:b431810374 . _:b431810414 "2"^^ . _:b431810369 . _:b7596349 . _:b7596347 _:b7596352 . _:b7596347 _:b7596353 . _:b7596339 . _:b431810409 "2"^^ . _:b431810368 . _:b7596347 _:b7596354 . . _:b431810408 "2"^^ . _:b431810371 . _:b431810368 . _:b7596340 "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." . _:b431810369 . _:b431810370 . _:b431810411 "2"^^ . _:b431810371 . _:b7596365 . _:b431810370 . _:b431810372 . _:b431810373 . _:b7596356 "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\u00B0C, a process which, in the absence of cholesterol in the membrane, causes significant" . _:b431810374 . _:b431810410 "2"^^ . . _:b431810375 . . _:b431810381 . _:b431810376 . _:b431810377 . _:b431810378 . _:b431810379 . _:b431810380 . _:b431810380 . _:b431810381 . _:b431810382 . _:b431810383 . _:b431810383 . _:b431810384 . . . _:b431810385 . _:b431810386 . _:b431810387 . _:b431810382 . _:b431810388 . _:b431810366 . . _:b431810389 . _:b431810390 . _:b431810367 . _:b431810391 . "10.1007%2Fs11095-010-0154-2" . _:b431810377 . _:b431810392 . _:b431810393 . _:b7596372 . _:b431810394 . _:b431810395 . _:b431810376 . _:b431810396 . _:b431810397 . _:b431810398 . _:b431810399 . _:b431810379 . _:b431810400 . _:b431810401 . _:b431810402 . _:b431810403 . _:b431810378 . _:b431810404 . _:b431810405 . _:b431810406 . _:b431810407 . _:b431810389 . _:b431810408 . _:b431810409 . . _:b431810410 . _:b431810411 . _:b7596366 "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\u00A0h of hyperthermia (>>12<<,14,15), the duration of the second heat trigger can be tailored accordingly." . . _:b431810388 . _:b431810412 . _:b431810413 . _:b431810414 . _:b7596367 "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\u00A0h of hyperthermia (12,>>14<<,15), the duration of the second heat trigger can be tailored accordingly." . _:b431810391 . _:b7596344 "hyperthermia" . . _:b431810390 . . _:b431810408 . . _:b431810385 . _:b7596350 . _:b431810369 . _:b431810384 . _:b7596370 . _:b7596349 "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." . _:b7596358 . _:b431810387 . _:b7596346 "Firm clinical proof of increased efficacy upon combining hyperthermia with chemotherapy has been obtained in the past 10\u00A0years 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." . _:b431810386 . . . _:b431810397 . _:b431810396 . _:b7596336 . _:b431810410 . _:b7596354 . _:b7596371 . _:b431810399 . _:b7596341 . . _:b431810364 . _:b431810398 .