Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

Abstract

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics.

Hyperbaric Oxygen Potentiates Doxil Antitumor Efficacy by Promoting Tumor Penetration and Sensitizing Cancer Cells

“…For instance, Zhu et al discovered that overexpression of CTGF in human mammary epithelial cells expressing LT, hTERT and H‐rasV12 tumor leads to an enlarged ratio of fibrous area as well as increased fibril content 31. Chauhan et al utilized losartan to inhibit the expression of CTGF in order to remodulate tumor ECM and achieve better drug delivery 18. Our data (Figure 1E,F) have demonstrated that HBO reduces the amount of HIF‐1α significantly, implying HBO might be able to inhibit collagen fibers deposition by interrupting HIF‐1α/CTGF/collagen pathway.…”

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

“…NI can be converted to hydrophilic 2-aminoimidazoles under a hypoxic environment via a single-electron reduction catalyzed by a series of nitroreductases coupled to bioreducing agents, such as NADPH, a plentiful coenzyme in tissues (24)(25)(26)(27). We conjugated amine-functionalized NI with HA (molecular mass of 300 kDa), which is well known to have excellent biocompatibility and biodegradability (28)(29)(30). As shown in Fig.…”

Targeting Inflammation to Improve Tumor Drug Delivery

“…Stress alleviation strategies are based on the concept that desmoplasia hinders proper drug delivery by compressing intratumoral blood vessels, and thus agents that relief the stress accumulated by ECM components will facilitate vessel decompression, improve perfusion, and enhance delivery of chemotherapy [2,14,15]. In fact, repurposing of common anti-fibrotic drugs to reduce collagen and/or hyaluronan levels when combined with cytotoxic drugs has shown to cause stress alleviation and improve overall survival of mice-bearing tumors [16][17][18]. Similarly, pharmacologic depletion of CAFs has shown to reduce intratumoral stresses, improving perfusion, drug delivery and overall survival in pancreatic and breast tumor models [19,20].…”