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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 BLZ-945 SCNs/Pt) that could spatially target tumor-associated macrophages (TAMs) and tumor cells for cancer chemoimmunotherapy. BLZ-945 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 BLZ-945 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.

Here we used a lipid-soluble Zn(II)-bis-dipicolylamine derivative as a membrane component to develop liposomal carriers that have potential to be targeted to phosphatidylserine (PS) rich surfaces on cancer cells and to preferentially kill cancer cells without using anticancer drugs. This DPA derivative (abbreviated as DPA-Cy3[22,22]) contains the fluorophore cyanine 3 (Cy3) and two 22-carbon chains that can be anchored into liposomal membrane bilayers. DPA-Cy3[22,22]/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) unilamellar vesicles (∼150 nm) showed selective binding to PS-containing liposomes as demonstrated by anion exchange chromatography. This binding does not result in vesicle fusion or aggregation. Flow cytometry showed that DPA-Cy3[22,22]/POPC liposomes have preferential binding to MCF-7 breast cancer cells over MCF-12A noncancer cells due to 3-7 times more PS exposures on MCF-7. The extent of liposome binding with MCF-7 cells was increased by two times after cells were pretreated with the apoptotic inducer camptothecin, which increased PS exposure to the cell surface. Moreover, our flow cytometry data also suggest that local cell membrane perturbations may occur upon liposome binding and internalization. This implies that DPA-Cy3[22,22]/POPC liposomes alone may have a PS-dependent cytotoxic effect. This assertion was supported by the cell proliferation assay, which showed that 9.1 mol % DPA-Cy3[22,22]/POPC liposomes exert cytotoxicity on MCF-7 cells 3.5 times higher than that on MCF-12A cells. These results indicate that DPA-Cy3[22,22]-containing liposomes hold great promise as efficient nano drug carriers.

The aqueous vanadium(III) (V(III)) speciation chemistry of two dipicolinate-type complexes and the insulin-enhancing effects of V-dipicolinate (V-dipic) complexes in three different oxidation states (V(III), V(IV), and V(V)) have been studied in a chronic animal model system. The characterization of the V(III) species was carried out at low ionic strength to reflect physiological conditions and required an evaluation of the hydrolysis of V(III) at 0.20 M KCl. The aqueous V(III)-dipic and V(III)-dipic-OH systems were characterized, and complexes were observed from pH 2 to 7 at 0.2 M KCl. The V(III)-dipic system forms stable 1:2 complexes, whereas the V(III)-dipic-OH system forms stable 1:1 complexes. A comparison of these complexes with the V-pic system demonstrates that a second ligand has lower affinity for the V(III), presumably reflecting bidentate coordination of the second dipic(2)(-) to the V(III). The thermodynamic stability of the [V(III)(dipic)(2)](-) complex was compared to the stability of the corresponding V(IV) and V(V) complexes, and surprisingly, the V(III) complexes were found to be more stable than anticipated. Oral administration of three V-dipicolinate compounds in different oxidation states {H[V(III)(dipic)(2)H(2)O].3H(2)O, [V(IV)Odipic(H(2)O)(2)].2H(2)O, and NH(4)[V(V)O(2)dipic]} and the positive control, VOSO(4), significantly lowered diabetic hyperglycemia in rats with streptozotocin-induced diabetes. The diabetic animals treated with the V(III)- or V(IV)-dipic complexes had blood glucose levels that were statistically different from those of the diabetic group. The animals treated with the V(V)-dipic complex had the lowest blood glucose levels of the treated diabetic animals, which were statistically different from those of the diabetic group at all time points. Among the diabetic animals, complexation to dipic increased the serum levels of V after the administration of the V(V) and V(IV) complexes but not after the administration of the V(III) complex when data are normalized to the ingested dose of V. Because V compounds differing only in oxidation state have different biological properties, it is implied that redox processes must be important factors for the biological action of V compounds. We observe that the V(V)-dipic complex is the most effective insulin-enhancing agent, in contrast to previous studies in which the V(IV)-maltol complex is the most effective. We conclude that the effectiveness of complexed V is both ligand and oxidation state dependent.

Chromium picolinate, [Cr(pic)(3)], is the second most popular nutritional supplement after calcium supplements. However, the supplement, unlike simple inorganic Cr(III) salts, has been shown in the presence of biological reducing agents in vitro to catalytically generate appreciable quantities of hydroxyl radicals, resulting in DNA damage. The complex has also been shown to be remarkably stable in vitro at neutral, basic, or weakly acidic pHs. Thus, the significance of this ability to generate hydroxyl radicals depends on whether the complex is absorbed by cells intact along with the stability and concentration of the complex in cells. Consequently, male Sprague Dawley rats have been injected with (51)Cr- and (3)H-labeled [Cr(pic)(3)]. The tissue distribution, urinary and fecal loss, and subcellular hepatocyte distribution and concentration of the labels suggest that [Cr(pic)(3)] has a lifetime of less than 1 day in vivo, minimizing the potential threat from the supplement itself.

Hematopoiesis is a lifelong cell renewal process regulated by a family of lineage specific hematopoietic growth factors. Several hematopoietic growth factors such as G-CSF, GM-CSF, and M-CSF have been clinically evaluated for enhancement of host defense in normal and immunocompromised patients and for the treatment of infectious diseases. This paper reports the structure-activity relationships of low molecular weight hematoregulatory peptides based on a nonapeptide (1, SK&F 107647). Like the macromolecular growth factors, these peptides modulate host defense. A molecular target for this class of compounds has not yet been identified. However, the structure-activity relationships established by this study implicate a very specific molecular recognition event that is pivotal for the biological activities of 1 and its analogues.