Tumor regression and potentiation of polymeric vascular disrupting therapy through reprogramming of a hypoxia microenvironment with temsirolimus

Although the polymeric vascular disrupting agent (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4) nanoparticles (CA4-NPs) has great potential to inhibit cancer growth, it is still a challenge to avert tumor recurrence and metastasis after treatment. It is mainly tightly associated with hypoxia induced by CA4-NPs, which can activate many downstream genes regulating tumor growth and metastasis. Herein, to relieve a tumor hypoxia microenvironment, the mTOR inhibitor temsirolimus was employed to modulate the tumor microenvironment when treated with CA4-NPs. In vitro MTT experiments strongly verified that the combination of temsirolimus with polymeric CA4-NPs exhibited an additive toxicity to 4T1 cells. An in vivo study with the 4T1 mammary adenocarcinoma model revealed that consistent with the proposed scenario, combination therapy with CA4-NPs plus temsirolimus suppressed tumor growth significantly more strongly compared to either CA4-NPs or temsirolimus monotherapy, and the inhibition rate to 4T1 tumor with a volume of 300 mm³ was 71%. The mechanism underling combination treatment was confirmed by western blotting and immunofluorescence staining, and the results demonstrated that temsirolimus could inhibit HIF1α expression. Thus, this work provides a mechanistic rationale for the use of VDAs in combination with the mTOR inhibitor to enhance anticancer efficacy, delaying tumor recurrence and inhibiting tumor metastasis.