Intratumoral accumulation

Intravenous administration of the thermally responsive ELP-rhodamine conjugate resiilted in localized precipitation in tumor tissue heated to 42°C, while no precipitation was observed when a control ELP-rhodamine conjugate, with a Tt of 70°C, was administered. Localized hyperthermia resiilted in a 2-fold increase in intratumoral accumulation... 

Figure 2. A. Intratumor accumulation of various Cr-tagged proteins in solid tumor-bearing mice o, neocarzinostatin (NCS) (12 kDa) , SMANCS (16 kDa, but known to bind to albumin) , ovomucoid (29 kDa) , bovine serum albumin (69kOa) , mouse serum albumin (68 kDa) , mouse immunoglobulin G (160 kDa). Radiolabeled proteins were injected i.v. at time zero. Values are based on radioactivity (cf. Fig. 2). The tumor model in both A and B was solid sarcoma S-180 in mice. (From ref. 26, with permission). B. Relationship of drug distribution and molecular size to plasma concentration, AUC (area under the concentration curve), renal clearance, and intratumor uptake as expressed by percentage of injected dose. Putative polymer drugs are 1-Tyr-HPMA-copolymers of various molecular sizes given i.v. at 1.8 xlO cpm. The tumor model was sarcoma S-180 in mice. (From ref. 28 with permission).

In recent years, a Cremophor-free formulation of paclitaxel has been developed, with the trade name Abraxane. It uses nanoparticle albumin-bound (nab) technology as a vehicle for the delivery of paclitaxel. Abraxane is a Cremophor-free, 130-nanometer particle form of paclitaxel, which delivers paclitaxel as a suspension of albumin particles in saline. It therefore avoids the adverse reactions that are associated with Cremophor EL. It does not need premedication with glucocorticoids and antihistamines. In animals albumin-bound paclitaxel has increased and prolonged antitumor activity and more effective intratumor accumulation of paclitaxel, compared with Cremophor-based paclitaxel [93 ]. It is currently licensed for second-line treatment of metastatic breast cancer. 

Zhang, M., Swofford, C.A., Forbes, N.S., 2014. Lipid A controls the rohnstness of intratumoral accumulation of attenuated Salmonella in mice. Int. J. Cancer 135, 647-657. 

Monsky WL et al (2002) Radio-frequency ablation increases intratumoral liposomal doxorubicin accumulation in a rat breast tumor model. Radiology 224 823-829... 

Kubota, R., Yamada, S., Kubota, K., Ishiwata, K., Tamahashi, N., and Ido, T. Intratumoral distribution of E-fiuorodeoxyglucose in vivo high accumulation in macrophages and granulation tissues studied by microautoradiography. J. Nucl. Med., 33 1972-1980, 1992. 

Injection of immunocompetent or nude mice with P8I5 mastocytoma cells transfected with the gene of the CC chemokine MCP-3/CCL7 resulted in peri-tumoral accumulation of DCs and intratumoral recruitment of neutrophils [66]. The expression of CCRl and CCR3 (MCP-3 receptors) on neutrophils may be upregulated by IFN-y induced in T and/or NK cells so that they can directly respond to MCP-3 [70] or, alternatively, recruited by secondary dovmstream mediators. Removal of neutrophils caused an evident delay of MCP-3-elicited tumor rejection, suggesting their cooperative role in tumor inhibition. 

In addition to the intertumoral heterogeneity, strong evidence has accumulated that parameters of the tumor micromflieu that affect radiosensitivity may also be heterogeneously distributed within the individual tumor (intratumoral heterogeneity). 

Fig. 4.20a-c. Cystic schwannoma. a,b Long-axis a gray-scale and b color Doppler 12-5 MHz US images over the radial nerve (arrowheads) at the arm with c MR-neurographic correlation show a rounded mass (arrows) with intratumoral cystic changes, related to accumulation of myxoid matrix, in continuity with the parent nerve (arrowheads). The tumor exhibits a hypervascular pattern made up of peripheral and central color Doppler signals... 

Ahmed M, Monsky WE, Girnum G, et al (2003) Radiofrequency thermal ablation sharply increases intratumoral liposomal doxorubicin accumulation and tumor coagulation. Cancer Res 63 6327-6333... 

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