Poor penetration of anti-cancer drugs into tumor tissue and to infiltrating tumor cells remains a major problem in therapy of solid tumors. Cancer therapeutics generally exhibit steep perivascular gradients, as they do not penetrate farther than 3-5 cell diameters from blood vessels. As a result, tumor cells that are distant from blood vessels receive little or no drug. Recently, we have identified tumor penetrating peptides (TPP) that trigger specific penetration of co-administered un-conjugated drugs deep into tumor and increase their therapeutic index. This work, published in PNAS, Cancer Cell and Science, pioneered the concept of tumor-penetrative drug delivery. Tumor penetrating peptides bind to tumor blood vessels and cause transport of various payloads (including drugs) outside the blood vessels and into tumor parenchyma. Importantly it is not necessary to couple a cargo to the peptide for tumor-selective delivery; free peptide activates a bulk transport pathway in the tumor which carries a co-injected drug or nanoparticle through the vascular wall and deep into the tumor tissue. Our technology goes beyond the state-of-the-art of targeted drug delivery platforms: it can be used to increase therapeutic index of unmodified approved cancer drugs, thus providing a potentially facilitated route to clinical applications.
Our current work focuses on generation of tumor penetrating peptides of novel specificities (using modular or screening-based approaches), developing a better mechanistic understanding of the tumor penetration process, and optimising nanocarriers for TPP-mediated delivery.
(A) Systemic drugs have poor selectivity and lack the ability to penetrate into glioma tissue. (B) gTPP enhance vascular exit and tissue penetration of co-injected drugs. B1 : gTPP are recruited to tumor vessels by a tumor homing sequence, followed by proteolytic cleavage and activation of a cryptic tissue-penetrating CendR element. B2: CendR element binds to neuropilin and triggers tumor penetration of a co-injected drug.