Neutrophils loaded with cationic liposomal paclitaxel migrate across the blood/brain barrier to deliver chemotherapeutic nanoparticles in the inflamed post-surgical tumour margin.
Glioblastoma (GBM), a type of malignant brain tumour, is one of the most lethal human cancers. The primary tumour is surgically removed and patients receive radiation and chemotherapy, but the tumour inevitably recurs, causing patient demise. Gliomas are highly invasive and surgery cannot remove the deeply infiltrated tumour cells in the surrounding brain parenchyma, and these remaining glioma cells become resistant to chemo and radiation therapies1. Moreover, there is growing evidence for the importance of the microenvironment in GBM growth and therapeutic resistance, and gliomas are known to produce cytokines in response to pro-inflammatory signals, which attract infiltrating leukocytes2,3 and participate in the maintenance of recurrence-initiating stem-like cancer cells4. Clearly, new therapeutic strategies are needed to prevent tumour treatment resistance and regrowth. Now, writing in Nature Nanotechnology, Jingwei Xue and colleagues turn the tables on the tumour and demonstrate that the post-operative inflammatory response induced by surgery in the remaining brain tissue adjacent to the tumour can be exploited for therapy through chemo-attraction of cell-based drug delivery5.
The blood/brain barrier (BBB) — a physiological structure that restricts which chemicals can enter the brain from the blood circulation — limits drug delivery into brain tumours, which is why most chemical compounds with demonstrated anticancer efficacy in other organs have limited effect in the brain. Because a number of cell types can actively cross the BBB and penetrate the brain parenchyma, autologous cell-mediated drug delivery has been explored for successfully transferring therapeutic drugs into brain tumours6,7. Although initial studies with immunocytes and neural and mesenchymal stem cells have provided proof-of-principle demonstrations, a number of obstacles are still to be overcome before this can move to testing in patients. Current limitations include drug-loading efficiency, toxicity of delivery drug for carrier cells, BBB crossing, abundance of autologous carrier cells from the treated patient, migration efficiency towards the tumour target, and efficient release of the drug at the target site.
Xue et al. hypothesized that neutrophils (NE) could be used as a new carrier for the delivery of nanoparticulated chemotherapeutics to suppress GBM recurrence after surgery. Neutrophils are the most abundant leukocyte population in human blood and they accurately home to sites of acute tissue injury and inflammation8. The researchers take advantage of the inherent properties of neutrophils to respond to chemokines released at sites of surgical tumour removal, which is a new approach to targeted therapy. To maximize therapeutic cargo-carrying capacity, the team generated a new type of 1,5-dioctadecyl-N-histidyl-l-glutamate-based cationic liposome (CL) and demonstrated efficient neutrophil loading and stable retention of paclitaxel (PTX), a traditional antimitotic cancer drug. Neutrophils loaded with PTX-CL appeared unharmed by their toxic cargo and retained their physiological activities: in response to inflammatory stimuli they exhibited a chemotactic response, and once inside the inflammatory region they actively generated superoxide and burst to release their PTX-CL cargo.
To test for in vivo efficacy, the team injected the PTX-CL-loaded neutrophils in the blood circulation of mice having undergone surgical resection of an experimentally generated GBM tumour (Fig. 1a). After systemic injection, the neutrophils homed to the surgical margin where inflammatory cytokines (TNFα and so on) are produced, and released PTX-CL, providing high local PTX delivery, which delayed glioma recurrence by killing the tumour cells and improved the survival of the mice (Fig. 1b). The treatment was not curative, possibly because the neutrophils did not reach all the islands of deeply infiltrated tumour cells beyond the surgical margin. Treatment of mice that did not undergo surgery led to limited neutrophil recruitment to the tumour and failed to extend survival, confirming that the therapeutic effect rests on post-surgical inflammation and that the baseline chemo-attractant activity of GBM is not strong enough to elicit potent neutrophil infiltration9. The treatment was well tolerated in mice, even though a significant amount of neutrophils homed to the spleen. Liver enzymes remained at normal levels in the serum, and main organs did not display evidence of necrosis.
Overall, these results are exciting because they show that neutrophils can be successfully harnessed to deliver therapeutically significant drug doses into the brain across the BBB. However, before this system can reach clinical trials, many challenges and limitations remain to be addressed. While the authors used three different GBM models (mouse G422, rat C6 and human U87MG cell lines), the first two are outbred models that can elicit host graft immune responses and the last one's origin is unknown10. Moreover, these models lack important pathobiological features of human GBM including cellular heterogeneity and invasive behaviour1,4. Further studies are needed to determine whether the brain areas well beyond the inflamed surgical cavity that are infiltrated by GBM cells could first be primed to express inflammatory cytokines before neutrophil delivery. It would be interesting to determine whether laser-directed microsurgical insults, chemo or radiation therapies could trigger targeted inflammation to further direct subsequent neutrophil delivery. Furthermore, the amount of therapeutic neutrophils used in the mouse model was about ten times higher than their total number in the circulation of a single mouse, suggesting that a large bolus would be needed in human patients. Optimal timing for pre-operative blood draw and potential perioperative side effects of neutrophil depletion are to be considered.
Despite the need for more work as explained above, it is important to emphasize that a neutrophil-based drug-delivery system has great potential for treatment beyond delaying post-operative recurrence of malignant gliomas, including several types of brain disorders such as multiple sclerosis, Alzheimer's disease, stroke and traumatic brain injury, which all involve neutrophil infiltration. This system could also be useful to deliver other types of therapeutic cargo such as cytokines, exosomes, viral particles and genes.
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Osuka, S., Van Meir, E. Neutrophils traffic in cancer nanodrugs. Nature Nanotech 12, 616–618 (2017). https://doi.org/10.1038/nnano.2017.82
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