Design and synthesis of selective polymeric nano-carriers for drug delivery and combination therapy
We combined emerging technologies to tackle an unsolved problem of selective targeting of anti-angiogenic drugs to tumor blood vessels. We designed, synthesized and characterized a water-soluble conjugate of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, cathepsin-cleavable linker and TNP-470, a very potent agent but highly toxic in clinical trials. This conjugate accumulated selectively in tumor vessels due to the enhanced permeability and retention (EPR) effect. It substantially enhanced and prolonged the anticancer activity of TNP-470. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. This new approach for targeting angiogenesis inhibitors specifically to the tumor vasculature provided a new strategy for the rational design of cancer therapies. This work was published in Nature Medicine in 2004. This is the first anti-angiogenic nanomedicine. Prior to this work, polymer therapeutics were targeted to cancer cells whereas the stromal compartment was neglected. Several patents were filed on this anti-angiogenic nanomedicine and it was licensed to a pharmaceutical company.
A second project focused on the hyperpermeability associated with angiogenic blood vessels compared to that of normal vessels. We found that several anti-angiogenic agents decrease vascular hyperpermeability of tumor blood vessels, reduce delayed-type hypersensitivity, and pulmonary edema induced by IL-2. We found that the mechanism was via inhibition of VEGF-induced phosphorylation of VEGFR-2, calcium influx, and RhoA activation in endothelial cells. These findings were published in Cancer Cell in 2005. This was the first time to identify the inhibition of VEGF-induced vessel hyperpermeability as the mechanism of action of many angiogenesis inhibitors. It suggests that this activity likely contributes to their anti-angiogenic effect, thus they can be used in the treatment of cancer, inflammation and other angiogenesis-dependent diseases.
Cancer Cell cover, 2005
The understanding that targeting only a single cellular compartment is not sufficient to foster a significant antitumor response, motivated my laboratory to focus on the development of combination nanomedicines targeting tumor and host compartments synergistically. This new treatment modality has demonstrated great promise in multiple tumor types, with enhanced antitumor activity and reduced toxicity.
Cellular uptake of HPMA copolymer ALN-TNP-470 conjugate into endothelial cells
- Satchi-Fainaro R, et al. (Folkman J), Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470, Nature Medicine, 10(3), 255-261 (2004). [PDF] [PubMed]
- Satchi-Fainaro R, et al. (Folkman J), Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin, Cancer Cell, 7(3), 251-261 (2005). (Cover feature). [PDF] [PubMed]
- Segal E, et al (Satchi-Fainaro R), Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics. PLoS One 2009, 4(4):e5233. [PDF] [PubMed]
- Miller K, et al. (Satchi-Fainaro R), Targeting bone metastases with bi-specific anticancer and anti-angiogenic polymer-alendronate-taxane conjugate, Angewandte Chemie-International Edition English 48(16), 2949 –2954 (2009) [PDF] [PubMed]
Markovsky E, Baabur-Cohen H, Satchi-Fainaro R, Anticancer polymeric nanomedicine bearing synergistic drug combination is superior to a mixture of individually-conjugated drugs, Journal of Controlled Release, 187: 145–157 (2014). (Cover feature). [PDF] [PubMed]