Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug

Abstract

Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behavior. Model TNPs comprised of a fluorescent platinum(IV) pro-drug and a clinically-tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumor associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload, and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA damaging Pt payload gradually releases to neighboring tumor cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials.

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

“…Typically, clodronate liposomes were used to deplete various kinds of macrophage/monocyte [22,23], such as primitive macrophages [24] microglia [25], Kupffer cells [26], alveolar macrophage [27], monocytes [25], tumor-associated macrophages [28,29]. Therefore, in this study, we packaged Fasudil in liposomes to realize the specific 4 targeting to macrophages/monocytes.…”

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

“…Although liposomal deposition is nonuniform and perivascular, primarily in stromal areas, gH2AX staining at 24-72 hours after liposome dosing in a pancreatic orthotopic model was broadly seen across all tumor areas but not the stroma (42). Nanoliposomal carriers may thus exhibit comparably faster drug release rates than therapeutic nanoparticles with a more erosive, slower release mechanism (27,43), which could possibly explain the lack of correlation between lesion response to nal-IRI and late binding events of FMX in this study. R2 and R2 Ã mapping are accepted clinical tools for evaluating tissue iron concentrations, both for iron overload disorders (44,45) and for tracking of ultrasmall superparamagnetic iron oxide particles (18,24,46).…”

Multifunctional nanoparticles for co-delivery of paclitaxel and carboplatin against ovarian cancer by inactivating the JMJD3-HER2 axis

“…Tumor xenograft mouse studies Tumors were not allowed to grow beyond a critical size of 4000 mm 3 , in accordance with the Institutional Animal Care guidelines. Once the maximum tumor volume was reached, the animal was euthanized with pentobarbital.…”

“…1 For the purpose of co-encapsulating dual therapies and then controlling release in the targeted area, several nano-formulation approaches have been attempted. [2][3][4] However, due to the significant differences between PAC and CAR in molecular weight and water solubility, the traditional nanocarriers for co-delivery of PAC and CAR often involving covalent bonding would have huge difficulties in maintaining the drug loading ratio and controlled simultaneous release. Therefore, there is an urgent need to develop novel nanovehicles with the aim of overcoming these difficulties.…”