A cell- surface polymer reptation mechanism for tumor transendothelial transport of macromolecules.
Polymer reptation is a process by which flexible linear polymers can migrate around obstacles and through pores and around other polymer molecules. It has successfully described quantitative behavior of polymer melts and has been invoked in explaining DNA separation according to length in sequencing gels. This mechanism may therefore be useful in delivering contrast agents or therapeutic drugs to tumors as these must traverse from the intravascular space through the tumor endothelial junction gaps and into the tumor. In this work, we show that polymers capable of weak interactions with tumor endothelium can translocate into the tumor interstitium at up to 9 times the rate of polymers without such cell-surface interactions. We propose a new mechanism by which the polymers diffuse along the cell surface and through cell junction gaps that occur in the tumor endothelium. This process can be halted in a number of ways that demonstrate that the surface interaction is essential for the higher transport rate. Alternative transport mechanisms are ruled out by further tests of polymer length scaling dependence, and by comparison of transport rates to those for globular constructs. Polymers of Gd-DTPA-polylysine and related backbones were investigated in an animal model of breast cancer and prostate cancer. Polymer lengths ranged from 30 nm to 300 nm, (from 100 to 700 lysine residues) and the polymer constructs had a cross section of approximately 1.2 nm in radius. Polymer uptake rate into tumors for an equivalent hydrodynamic size globular macromolecule was some 135 times larger demonstrating the importance of this transport mechanism compared to free diffusion of globular macromolecules through the endothelium junction pores. The polymer length scaling, with monomer number N, on rate of tumor transport goes as N(-1), which rejects alternative transport processes such as pinocytosis, active transport, and particle like center of mass diffusion through pores. This N(-1) scaling implies a cell-surface assisted polymer reptation process. This new transport mechanism allows very strong discrimination of aggressive tumors from nonaggressive tumors in animal model studies.
Uzgiris
Egidijus E
EE
Physics Department, Rensselaer Polytechnique Institute, Troy, NY 12180, USA. euzgiris@nycap.rr.com
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D002463:Cell Membrane Permeability; D003287:Contrast Media / Q000737:chemistry* / Q000378:metabolism; D004058:Diffusion; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D019786:Gadolinium DTPA / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000378:metabolism*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D051381:Rats
D003287:Contrast Media; D011108:Polymers; C068674:polylysine-(Gd-DTPA); D011107:Polylysine; D019786:Gadolinium DTPA