Table 1.

Examples of nanoparticle delivery mechanisms across tumor vasculature.

Method	Year first described	Classification	Description	References
Active targeting liposomes	1979	Biological	Involves the attachment of specific antibodies or other molecules to the nanoparticle surface for targeting of complementary receptors on cancer cells. The tumor penetrating peptide, iRGD, and its derivatives, are widely used examples.	[64,65,202,203]
Heat treatment	1979	Physical	Local heating of tumors several degrees above the average temperature has been shown to significantly increase the extravasation of nanoparticles until vessel destruction occurs. Photosensitive and paramagnetic nanoparticles are being studied to improve these effects.	[66,67,204]
Erythrocyte hitchhiking	1987	Biological/cell mediated	This process has evolved from erythrocytes being removed from the patient and loaded with drugs and readministered to removed erythrocytes being conjugated with drug carrying nanoparticles and readministered to localize at the nearest downstream organ from the injection site. Work has also been done on coating nanoparticles with intact membranes from erythrocytes containing the typically expressed surface proteins for improved circulation.	[23,70,71]
Vascular normalization	1996	Biological	This is an extension of typical antiangiogenic treatments which aim to make tumor vasculature more functionally similar to normal vasculature by removing excessive endothelial cells that make up immature blood vessels, for a less constricted delivery of therapeutics to tumors before cutting off the blood supply to the tumor. Antiangiogenic nanoparticles loaded with anticancer drugs are being explored as a method of simultaneously normalizing tumor vasculature and deliver cytotoxic drugs.	[72,73,205]
Ultrasound	1999	Physical	The tensile pressure from ultrasonic waves directed at tumors has been shown to cause blood vessel perforation via cavitation, as well as microconvection that results in higher extravasation. Ultrasound has also been used to cause the release of drugs such as doxorubicin from liposomes upon insonation, possibly through the formation of transient pores or other membrane defects	[76,77]
Leukocyte hitchhiking	2005	Biological/cell mediated	Antigen-specific T cells can be removed and loaded with viral vectors, that once readministered, will target tumors and transfer the viral vectors. Intravenously administered nanoparticles can be phagocytosed by monocytes, which travel to the tumor microenvironment and differentiate into tumor-associated macrophages (TAMs) to migrate into the hypoxic tumor core. Near-IR irradiation can be directed toward the tumor, which may destroy the TAMs and heat up the nanoparticles to destroy surrounding tissues. The membranes of leukocytes can be coated onto nanoparticles in a similar manner as discussed above with erythrocytes, which could be applied to tumor targeting.	[7,79,206]