Intratumoral distribution

Steyger, P.S. Baban, D.F. Brereton, M. Ulbrich, K. Seymour, L.W. Intratumoral distribution as a determinant of tumor responsiveness to therapy using polymer-based macromolecular prodrugs. Journal of Controlled Release... 

For an observation of intratumor distribution of liposomes, Dil Cl 8 of the quantity equivalent to 1 mol% of DSPC was added to the liposome. Dil CIS-labeled PEG-lip and PEG-APRPG-lip were composed of DSPC, cholesterol, DSPE-PEG and DSPE-PEG-APRPG and Dil CIS (10 5 1 0.1 as molar ratio). 

Fig. 2. Intratumoral distribution of DilCIS-labeled liposomes in the orthotopic pancreatic tumors. Mice with orthotopic pancreatic tumor were injected with PEG-Lip or APRPG-PEG-Lip labeled with Dil Cl 8 via a tail vein at the day 3,9, and 18 after tumor implantation. At 2 h after injection of fluorescence-labeled liposomes, frozen-sections of each tumor were prepared. Green portions indicate CD31-positive regions, red portions liposomal distribution, and yellow portions show the localization of liposomes at the site of vascular endothelial cells. Scale bar represents lOOgm. Reproduced with permission from (7)...

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. 

Maeda N, Miyazawa S, Shimizu K, Asai T, Yonezawa S, Kitazawa S, Namba Y, Tsukada H, Oku N. Enhancement of anticancer activity in antineovascular therapy is based on the intratumoral distribution of the active targeting carrier for anticancer drugs. Biol Pharm Bull 2006 29 1936 1940. 

Another essential question addresses the reproducibility of the intratumoral distribution of hypoxia. In a recent study Nehmeh et al. (2008) evaluated the dynamics of the FMISO uptake in PET over 3 days in 14 patients with untreated head and neck tumors. The authors describe variability in spatial hypoxia tracer uptake. Only 6/13 patients had well-correlated intratumoral distributions of FMISO, suggestive of chronic hypoxia. 

It is quite possible that a treatment may be initiated using, for example, intratumoral injections to deliver a gene, which may subsequently be administered systemically. As a considerable amount of relevant information will have already been generated to support the intratumoral route, this would be another case for doing bridging studies. Comparative distribution studies will help to identify how much more safety evaluation may be required. 

Heise CC, Williams A, Olesch J, et al. Efficacy of a replication-competent adenovirus (ONYX-015) following intratumoral injection intratumoral spread and distribution effects. Cancer Gene Ther 1999 6 499-504. 

Callahan, D. J. Liu, W. E. Li, X. H. Dreher, M. R. Hassouneh, W. Kim, M. Marsza-lek, P. Chilkoti, A. Triple stimulus-responsive polypeptide nanoparticles that enhance intratumoral spatial distribution. Nano Lett. 2012,12, 2165-2170. 

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). 

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).

Lee H, Fonge H, Hoang B, Reilly RM, Allen C (2010) The effects of particle size and molecular targeting on the intratumoral and subcellular distribution of polymeric nanoparticles. Mol Pharm 7(4) 1195-1208... 

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