Cavitation-mediated extravasation and transtumoral drug delivery by microstreaming: What role do the gas nuclei and the physical properties of the therapeutic play?

For effective cancer therapy, therapeutic agents must extravasate from the blood stream into the tumour mass, then overcome the elevated intratumoural pressure and dense extracellular matrix to reach each and every cancer cell. Several recent studies have suggested that inertial cavitation in the absence or presence of artificial cavitation nuclei can significantly enhance the delivery, penetration, and distribution of small-molecule or nanoparticulate therapeutic agents into tumors. We first present a comparison of the reported enhancements in delivery achieved for a range of frequencies and therapeutic sizes without or with pre-seeding of cavitation, with particular emphasis on the potential role of cavitation persistence and spatial distribution. With microstreaming hypothesized to be the dominant transport mechanism for drug delivery, the likely benefit of using sub-micron cavitation nucleation agents capable of extravasating alongside the therapeutic, rather than microbubbles confined to the blood pool, is then investigated. Lastly, potential physical and biological modification strategies capable of enhancing the transport of therapeutics by cavitation-microstreaming are discussed, and compared in terms of their relative delivery efficacies in vivo.