Extravasation of polymeric nanomedicines across tumor vasculature ☆ Michael K. Danquah a , Xin A. Zhang b , Ram I. Mahato a, ⁎ a Department of Pharmaceutical Sciences, 19. South Manassas St., Memphis, TN, 38103-3308, USA b Department of Medicine, University of Tennessee Health Science Center, 19. South Manassas St., Memphis, TN, 38103-3308, USA abstract article info Article history: Received 13 October 2010 Accepted 30 November 2010 Available online 6 December 2010 Keywords: Extravasation Drug delivery Nanomedicines Tumor vasculature Tumor targeting Tumor microvasculature is fraught with numerous physiological barriers which hinder the efficacy of anticancer agents. These barriers include chaotic blood supply, poor tumor vasculature permeability, limited transport across the interstitium due to high interstitial pressure and absence of lymphatic network. Abnormal microvasculature also leads to hypoxia and acidosis which limits effectiveness of chemotherapy. These barriers restrict drug or drug carrier extravasation which hampers tumor regression. Targeting key features of the tumor microenvironment such as tumor microvessels, interstitial hypertension and tumor pH is a promising approach to improving the efficacy of anticancer drugs. This review highlights the current knowledge on the distinct tumor microenvironment generated barriers which limit extravasation of drugs and focuses on modalities for overcoming these barriers using multi-functional polymeric carriers. Special attention is given to utilizing polymeric nanomedicines to facilitate extravasation of anticancer drugs for future cancer therapy. © 2010 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 2. Microenvironment of solid tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 2.1. Interstitial hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 2.2. Low extracellular pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625 2.3. Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626 2.4. Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626 2.5. Tumor–stromal cell interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 2.6. Cancer stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 2.7. Abnormal lymphatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 3. Anatomical pathways of macromolecular extravasation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 3.1. Macroscopic arrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 3.2. Tumor blood vessel wall structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 3.2.1. Continuous capillaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 3.2.2. Fenestrated capillaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 3.2.3. Discontinuous capillaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 3.3. Endothelial openings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 3.4. Vesiculo-vacuolar organelle mediated extravasation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 4. Extravasation across microvascular wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 5. Barriers to drug delivery across tumor capillaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629 5.1. Chaotic blood supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629 5.2. Poor permeability of tumor vasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629 5.3. Limited transport across the interstitium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629 Advanced Drug Delivery Reviews 63 (2011) 623–639 ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Target Cell Movement in Tumor and Cardiovascular Diseases". ⁎ Corresponding author. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 South Manassas, CRB RM 224, Memphis, TN 38103-3308, USA. Tel.: +1 901 448 6929; fax: +1 901 448 2099. E-mail address: rmahato@uthsc.edu (R.I. Mahato). URL: http://www.uthsc.edu/pharmacy/rmahato (R.I. Mahato). 0169-409X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2010.11.005 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr