Drug-loaded sickle cells programmed ex vivo for delayed hemolysis target hypoxic tumor microvessels and augment tumor drug delivery

JOURNAL OF CONTROLLED RELEASE

卷:171

Article

Choe, Se-woon¹  Terman, David S.²  Rivers, Angela E.³  Rivera, Jose⁴  Lottenberg, Richard⁵  Sorg, Brian S.⁶ 

[1] Gumi Elect & Informat Technol Res Inst, Gumi, South Korea

[2] Jenom Res Inst, Mol Genet Program, Carmel, VA USA

[3] Univ Illinois, Coll Med, Div Pediat Hematol Oncol, Chicago, IL USA

[4] Univ Illinois, Dept Bioengn, Urbana, IL 61801 USA

[5] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL USA

[6] NCI, NIH, Bethesda, MD 20892 USA

关键词: Blood;    Cancer;    Carrier;    Chemotherapy;    Particle;    Photosensitizer;   

DOI  :  10.1016/j.jconrel.2013.07.008

来源: Elsevier

【 摘 要 】

Selective drug delivery to hypoxic tumor niches remains a significant therapeutic challenge that calls for new conceptual approaches. Sickle red blood cells (SSRBCs) have shown an ability to target such hypoxic niches and induce tumoricidal effects when used together with exogenous pro-oxidants. Here we determine whether the delivery of a model therapeutic encapsulated in murine SSRBCs can be enhanced by ex vivo photosensitization under conditions that delay autohemolysis to a time that coincides with maximal localization of SSRBCs in a hypoxic tumor. Hyperspectral imaging of 4T1 carcinomas shows oxygen saturation levels <10% in a large fraction (commonly 50% or more) of the tumor. Using video microscopy of dorsal skin window chambers implanted with 4T1 tumors, we demonstrate that allogeneic SSRBCs, but not normal RBCs (nRBCs), selectively accumulate in hypoxic 4T1 tumors between 12 and 24 h after systemic administration. We further show that ex vivo photo-oxidation can program SSRBCs to postpone hemolysis/release of a model therapeutic to a point that coincides with their maximum sequestration in hypoxic tumor microvessels. Under these conditions, drug-loaded photosensitized SSRBCs show a 3-4 fold greater drug delivery to tumors compared to non-photosensitized SSRBCs, drug-loaded photosensitized nRBCs, and free drug. These results demonstrate that photo-oxidized SSRBCs, but not photo-oxidized nRBCs, sequester and hemolyze in hypoxic tumors and release substantially more drug than photo-oxidized nRBCs and non-photo-oxidized SSRBCs. Photo-oxidation of drug-loaded SSRBCs thus appears to exploit the unique tumor targeting and carrier properties of SSRBCs to optimize drug delivery to hypoxic tumors. Such programmed and drug-loaded SSRBCs therefore represent a novel and useful tool for augmenting drug delivery to hypoxic solid tumors. Published by Elsevier B.V.

【 授权许可】

Free