Improvement of Anticancer Drug Release by Cobalt Ferrite Magnetic Nanoparticles through Combined pH and Temperature Responsive Technique.

This work reports the application possibilities of cobalt ferrite (CoFe2 O4 ) magnetic nanoparticles (CFMNPs) for stimuli responsive drug delivery by magnetic field induced hyperthermia technique. The CFMNPs were characterized by X-ray diffraction (XRD) with Rietveld analysis, field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), selected area electron diffraction (SAED), fourier transform infrared spectroscopy (FTIR), thermogravimetry and differential thermal analysis (TG-DTA), vibrating sample magnetometer (VSM) and superconducting quantum interference device (SQUID) magnetometry. Particles were functionalized with folic acid (FA) by EDC-NHS coupling method and loaded with anticancer drug (DOX) by activated folate ions. The drug release was studied as a function of time at two different temperatures (37 and 44 °C) under pH∼5.5 and 7. It was observed that the drug release rate is higher at elevated temperature (44 °C) and acidic pH∼5.5 as compared to our normal body temperature and pH∼7 using the CFMNPs. This way, we have developed a pH and temperature sensitive drug delivery system, which can release the anticancer drug selectively by applying ac magnetic field as under ac field particles are heated up. We have calculated the amount of heat generation by the particles around 1.67 °C per second at ∼600 Hz frequency. By MTT assay on cancer cell and normal cell, it was confirmed that CFMNPs are nontoxic and biocompatible in nature, which assures that our synthesized particles can be successfully used in localized cancer treatment by stimuli responsive drug delivery technique.

BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFß Signaling to Durably Suppress Tumor Growth.

The EGFR and TGFß signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFß could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFßRII. The TGFß "trap" fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGFß by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer-cell activation, while suppressing VEGF secretion. In addition, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFß "trap." TGFß in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFßRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR-expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy. SIGNIFICANCE: The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFß to induce immune activation and to suppress tumor growth.