Abstract
PurposeIntravenously (i.v.) administered nanomedicines have the potential for tumour targeting due to the enhanced permeability and retention (EPR) effect, but in vivo tumour models are rarely calibrated with respect to functional vascular permeability and/or mechanisms controlling intratumoural drug release. Here the effect of tumour type and tumour size on EPR-mediated tumour localisation and cathepsin B-mediated drug release was studied.MethodsEvans Blue (10 mg/kg) and an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–doxorubicin (Dox) conjugate (FCE28068) (5 mg/kg Dox-equiv) were used as probes and tumour levels (and Dox release) measured at 1 h after i.v. administration in a panel of murine and human xenograft tumours.ResultsEvans Blue and FCE28068 displayed similar tumour levels in the range of 2–18 % dose/g at 1 h for B16F10 and L1210. Approximately half of the tumour models evaluated exhibited tumour size-dependent accumulation of FCE28068; smaller tumours had the highest accumulation. Administration of free Dox (5 mg/kg) produced tumour levels of <2.5 % dose/g independent of tumour size. Whereas the degree of EPR-mediated targeting showed ~12-fold difference across the tumour models evaluated, Dox release from FCE28068 at 1 h displayed ~200-fold variation.ConclusionsMarked heterogeneity was seen in terms of EPR effect and Dox release rate, underlining the need to carefully calibrate tumour models used to benchmark nanomedicines against known relevant standard agents and for optimal development of strategies for late pre-clinical and clinical development.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-013-2209-7) contains supplementary material, which is available to authorized users.
Highlights
An increasing number of nanomedicines, including liposomes, polymer conjugates, block copolymer micelles, nanoparticles and other complex hybrid technologies, are being developed as anticancer therapeutics, imaging agents and theranostics
Marked heterogeneity was seen in terms of enhanced permeability and retention (EPR) effect and Dox release rate, underlining the need to carefully calibrate tumour models used to benchmark nanomedicines against known relevant standard agents and for optimal development of strategies for late pre-clinical and clinical development
When the tumour levels were expressed as % dose for Evans Blue (Fig. 2a, c), tumour levels increased in an approximately linear fashion with increasing tumour size up to a maximum of 4–6 % dose/tumour for the B16F10 model and *15 % dose/tumour for the L1210 model (Fig. 2a, c)
Summary
An increasing number of nanomedicines, including liposomes, polymer conjugates, block copolymer micelles, nanoparticles and other complex hybrid technologies, are being developed as anticancer therapeutics, imaging agents and theranostics (reviewed in [1,2,3,4]). (i.v.) administered long-circulating nanosized constructs have long been known to exhibit passive tumour targeting due to the enhanced permeability and retention (EPR) effect [5, 6]. This phenomenon has been demonstrated in many in vivo tumour models and the features of polymer conjugates [7, 8], nanoparticles [4] and block copolymer micelles [9] governing extravasation, as well as tumour characteristics [10] regulating the efficiency of the process have been discussed. A diverse array of tumour pathophysiological features regulate the efficiency of EPR-mediated tumour targeting including heterogeneity of intratumoural blood flow, angiogenic vascular permeability, tumour microenvironment including extracellular matrix features, interstitial pressure and lymphatic drainage, and no single biomarker adequately predicts tumour targeting and/or antitumour activity [14]
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