Elastin-like polypeptides: The influence of its molecular weight on local hyperthermia-induced tumor accumulation

• ELP is thermally responsive polypeptides that can be targeted to tumor sites with local hyperthermia.
• Three sizes of Bac-ELPs (43, 63, 122 kDa) have been designed for this study.
• They have no significant differences in thermal properties and pharmacokinetic profiles.
• Larger Bac-ELPs showed enhanced accumulation in tumors with the application of local hyperthermia.
• Larger Bac-ELPs would be optimal for the improved tumor accumulation with local hyperthermia.

Elastin-like polypeptides (ELP) are thermally responsive polypeptides that are soluble in solutions at 37 °C, but which aggregate above 42 °C. ELP can be used as effective carrier systems of anticancer molecules, because they can be targeted to tumor sites through the application of local hyperthermia. Since molecular size largely influences how successfully therapeutic agents can cross the vasculatures of tumors, it was crucial to determine an optimal molecular size. In this study, we designed and evaluated three ELP macromolecules with varying molecular weights (43, 63, and 122 kDa), with the goal of determining which would optimize the ELP drug delivery system. The N-terminus of the ELP macromolecule was modified with the cell penetrating peptide Bac to enhance intratumoral and intracellular uptake, and it was also confirmed that each polypeptide had the target transition temperature of 37–42 °C and the results of the studies, using tumor-bearing mice, showed that the tumor accumulations increased in the case of all three peptides when local hyperthermia was applied, but that the elimination patterns from these tumors varied according to peptide size. Local hyperthermia was found to produce prolonged retention of all ELP conjugates in tumors except Bac-ELP43. In addition, the pharmacokinetic analysis showed that two larger polypeptides with 63 and 122 kDa have increased AUC in comparison with the 43 kDa polypeptide. These results suggest that, when combined with local hyperthermia, the larger ELP conjugates (63 and 122 kDa) have advantages over the smaller Bac-ELP43 polypeptide in terms of enhanced permeability and higher retention effects.

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