Targeted depletion of tumour-associated macrophages by an alendronate-glucomannan conjugate for cancer immunotherapy.

Abstract

Tumour-associated macrophages (TAMs) are a set of macrophages residing in the tumour microenvironment. They play essential roles in mediating tumour angiogenesis, metastasis and immune evasion. Delivery of therapeutic agents to eliminate TAMs can be a promising strategy for cancer immunotherapy but an efficient vehicle to target these cells is still in pressing need. In this study, we developed a bisphosphonate-glucomannan conjugate that could efficiently target and specifically eliminate TAMs in the tumour microenvironment. We employed the polysaccharide from Bletilla striata (BSP), a glucomannan affinitive for macrophages that express abundant mannose receptors, to conjugate alendronate (ALN), a bisphosphonate compound with in vitro macrophage-inhibiting activities. In both in vitro and in vivo tests, the prepared ALN-BSP conjugate could preferentially accumulate in macrophages and induced them into apoptosis. In the subcutaneous S180 tumour-bearing mice model, the treatment using ALN-BSP effectively eliminated TAMs, remarkably inhibited angiogenesis, recovered local immune surveillance, and eventually suppressed tumour progression, without eliciting any unwanted effect such as systematic immune response. Interestingly, ALN alone failed to exhibit any anti-TAM activity in vivo, probably because this compound was susceptible to the mildly acidic tumour microenvironment. Taken together, these results demonstrate the potential of ALN-BSP as a safe and efficient tool targeted at direct depletion of TAMs for cancer immunotherapy.

DOI: 10.1016/j.biomaterials.2014.09.007

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Cite this paper

@article{Zhan2014TargetedDO, title={Targeted depletion of tumour-associated macrophages by an alendronate-glucomannan conjugate for cancer immunotherapy.}, author={Xiudan Zhan and Lixin Jia and Yiming Niu and Haixia Qi and Xiuping Chen and Qingwen Zhang and Junfeng Zhang and Yitao Wang and Lei Dong and Chunming Wang}, journal={Biomaterials}, year={2014}, volume={35 38}, pages={10046-57} }