Tumor targeting based on the effect of enhanced permeability and retention (EPR) and the mechanism of receptor-mediated endocytosis (RME)

Tanaka, Tetsuro; Shiramoto, Shoichi; Miyashita, Masahide; Fujishima, Yuko; Kaneo, Yoshiharu

doi:10.1016/j.ijpharm.2003.09.050

Cited by 186 publications

(90 citation statements)

References 49 publications

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“…These data provide evidence of the immunobumin's specific tumor uptake. While HSA had some tumor retention, at this point we can only speculate this is a result of blood flow/permeability activity and the presence of albumin-binding proteins on the cell surface [20,21].…”

Section: Discussionmentioning

confidence: 83%

Biodistribution and tumor imaging of an anti-CEA single-chain antibody–albumin fusion protein

Yazaki

Kassa

Cheung

et al. 2008

Nuclear Medicine and Biology

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Albumin fusion proteins have demonstrated the ability to prolong the in vivo half-life of small therapeutic proteins/peptides in the circulation and thereby potentially increase their therapeutic efficacy. To evaluate if this format can be employed for antibody-based imaging, an anticarcinoembryonic antigen (CEA) single chain antibody-albumin fusion protein was designed, expressed and radiolabeled for biodistribution and imaging studies in athymic mice bearing human colorectal carcinoma LS-174T xenografts. The [ 125 I]-T84.66 fusion protein demonstrated rapid tumor uptake of 12.3% injected dose per gram (ID/g) at 4 hr that reached a plateau of 22.7 %ID/g by 18 hr. This was a dramatic increase in tumor uptake compared to 4.9 %ID/g for the scFv alone. The radiometal [ 111 In]-labeled version resulted in higher tumor uptake, 37.2 %ID/g at 18 hr, that persisted at the tumor site with tumor: blood ratios reaching 18:1 and with normal tissues showing limited uptake. Based on these favorable imaging properties, a pilot [ 64 Cu]-PET imaging study was performed with promising results.The anti-CEA T84.66 scFv-albumin fusion protein demonstrates highly specific tumor uptake that is comparable to cognate recombinant antibody fragments. The radiometal labeled version, which shows lower normal tissue accumulation than these recombinant antibodies, provides a promising and novel platform for antibody-based imaging agents.

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Section: Discussionmentioning

confidence: 83%

Biodistribution and tumor imaging of an anti-CEA single-chain antibody–albumin fusion protein

Yazaki

Kassa

Cheung

et al. 2008

Nuclear Medicine and Biology

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“…For solid tumours, nanosized delivery vehicles can passively target cancers through use of the enhanced permeability and retention (EPR) effect. The EPR effect arises due to differences between the blood vessels surrounding the tumours and those of normal tissues [3]. The blood vessels in tumours are irregular in shape, dilated, leaky or defective and the endothelial cells in the vessels are poorly aligned [4].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of anionic half generation 3.5–6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin

Kirkpatrick

Plumb

Sutcliffe

et al. 2011

Journal of Inorganic Biochemistry

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Title: Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin Article Type: Regular Paper Keywords: cancer; platinum; PAMAM dendrimer; cisplatin; guanosine; cytotoxicity; diffusion NMR. Abstract: Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion 1H NMR y and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH3)2}molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'GMP at temperatures of 60 oC for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%. We have revised the manuscript taking into account all your listed corrections and stylistic requirements.As siDNA and PBS were used only once in the manuscript we have now written these in full and not used them as abbreviations.For simplicity, we have made figure 5 just black and white and have changed the figure caption to reflect this. G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'GMP at temperatures of 60 o C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tu...

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“…This pH shift corresponds to the pH shift observed in malignant tissues from that of normal tissues and hence is a valuable trigger for releasing encapsulated drugs at the target site. Further, the effect of enhanced permeability and retention (EPR) and the mechanism of receptor-mediated endocytosis (RME) are thought to be useful mechanisms for targeting macromolecular drugs specifically to tumor tissues on a vasculolymphatic level [144].…”

Section: Ph-sensitive Gelsmentioning

confidence: 99%

Smart polymeric gels: Redefining the limits of biomedical devices

Chaterji

Kwon

Park

2007

Progress in Polymer Science

552

364

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This review describes recent progresses in the development and applications of smart polymeric gels, especially in the context of biomedical devices. The review has been organized into three separate sections: defining the basis of smart properties in polymeric gels; describing representative stimuli to which these gels respond; and illustrating a sample application area, namely, microfluidics. One of the major limitations in the use of hydrogels in stimuli-responsive applications is the diffusion rate limited transduction of signals. This can be obviated by engineering interconnected pores in the polymer structure to form capillary networks in the matrix and by downscaling the size of hydrogels to significantly decrease diffusion paths. Reducing the lag time in the induction of smart responses can be highly useful in biomedical devices, such as sensors and actuators. This review also describes molecular imprinting techniques to fabricate hydrogels for specific molecular recognition of target analytes. Additionally, it describes the significant advances in bottom-up nanofabrication strategies, involving supramolecular chemistry. Learning to assemble supramolecular structures from nature has led to the rapid prototyping of functional supramolecular devices. In essence, the barriers in the current performance potential of biomedical devices can be lowered or removed by the rapid convergence of interdisciplinary technologies.

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Tumor targeting based on the effect of enhanced permeability and retention (EPR) and the mechanism of receptor-mediated endocytosis (RME)

Cited by 186 publications

References 49 publications

Biodistribution and tumor imaging of an anti-CEA single-chain antibody–albumin fusion protein

Biodistribution and tumor imaging of an anti-CEA single-chain antibody–albumin fusion protein

Evaluation of anionic half generation 3.5–6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin

Smart polymeric gels: Redefining the limits of biomedical devices

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