Spatial Targeting of Tumor-Associated Macrophages and Tumor Cells with a pH-Sensitive Cluster Nanocarrier for Cancer Chemoimmunotherapy

Abstract

Chemoimmunotherapy, which combines chemotherapeutics with immune-modulating agents, represents an appealing approach for improving cancer therapy. To optimize its therapeutic efficacy, differentially delivering multiple therapeutic drugs to target cells is desirable. Here we developed an immunostimulatory nanocarrier (denoted as SCNs/Pt) that could spatially target tumor-associated macrophages (TAMs) and tumor cells for cancer chemoimmunotherapy.SCNs/Pt undergo supersensitive structure collapse in the prevascular regions of tumor tissues and enable the simultaneous release of platinum (Pt)-prodrug conjugated small particles and BLZ-945, a small molecule inhibitor of colony stimulating factor 1 receptor (CSF-1R) of TAMs. The released BLZ-945 can be preferentially taken up by TAMs to cause TAMs depletion from tumor tissues, while the small particles carrying Pt-prodrug enable deep tumor penetration as well as intracellularly specific drug release to kill more cancer cells. Our studies demonstrate that SCNs/Pt outperform their monotherapy counterparts in multiple tumor models. The underlying mechanism studies suggest that the designer pH-sensitive codelivery nanocarrier not only induces apoptosis of tumor cells but also modulates the tumor immune environment to eventually augment the antitumor effect of CD8 cytotoxic T cells through TAMs depletion.

Recent advances in metallopolymer-based drug delivery systems

“…It turned out that the customized pH-sensitive co-delivery nanocarriers not only induce tumor cell apoptosis, but also modulate the tumor immune environment and eventually augmented the antitumor effect of CD8 + cytotoxic T cells due to TAM depletion. 232 A method was developed for the manufacture of tastemasked oral DDS based on CP, Fe-4,4 0 -bipyridine (Fe-bipy) complex, that regulated the release of unpleasant drug taste by changing the pH value in the physiological environment of the alimentary canal (Fig. 26).…”

Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy

“…In addition, colony‐stimulating factor 1 receptor (CSF‐1R), which is highly expressed on the surface of macrophages and monocytes, is an important factor of their differentiation and survival. Based on the essential role of CSF‐1R, a pH‐sensitive nanocarrier was developed for the codelivery of platinum prodrug‐conjugated NPs and a CSF‐1R inhibitor (BLZ‐945), which caused the spatial targeting of tumor cells and TAMs for cancer chemo‐immunotherapy . Similarly, Qian et al developed dual‐targeting NPs against M2 macrophages by functionalizing them with M2pep and α‐peptide (a scavenger receptor B type 1‐targeting peptide) .…”

Progress on Modulating Tumor‐Associated Macrophages with Biomaterials

“…Isolated TAMs from treated tumors had substantially higher iNOS, CCR7, and M1‐marker expression, compared to controls. Similarly, “ultra‐pH‐sensitive cluster nanobombs” (SCNs), composed of poly(ethylene glycol)‐ b ‐poly(2‐azepane ethyl methacrylate)‐modified PAMAM dendrimers (PEG‐ b ‐PAEMA‐PAMAM), released cargo specifically in the low tumor pH environment . At the low tumor pH, the SCNs disintegrated and rapidly released their cargo: 1) platinum (Pt) prodrug small particles (≈10 nm) and 2) BLZ‐945, a CSF‐1R small molecule inhibitor.…”