Thin film growth and characterization of the electron- doped superconductor Sm̳2̳-x̳C̳ex̳CuO̳4̳-̳y

Sm̳2̳-x̳C̳ex̳CuO̳4̳-̳y belongs to a class of materials known as electron-doped superconductors (Ln̳2̳-x̳Mx̳CuO̳4̳-̳y;Ln = Pr, Nd, Sm, Eu; M = Ce, Th) and has a moderately high superconducting critical temperature, T̳c, of ̃ 20 K at optimal doping (x = 0.15). The trivalent rare earth site is doped with tetravalent Ce or Th; hence the name "electron-doped". Sm̳2̳-x̳C̳ex̳CuO̳4̳-̳y also exhibits a unique magnetic structure at low temperatures (T < 6 K) due to the antiferromagnetic ordering of the Sm³⁺ ions. In this study, thin films of the electron-doped superconductor Sm̳2̳-x̳C̳ex̳CuO̳4̳-̳y (SCCO) have been grown by pulsed laser deposition (PLD) for a cerium concentration range of x = 0.13 to x = 0.19. The films have been characterized through x-ray diffraction, electrical transport, and thermal transport measurements. A temperature versus cerium content (T-x) phase diagram has been constructed from the electrical transport measurements and yields a superconducting region similar to that of two of the other electron-doped superconductors Nd̳2̳-x̳C̳ex̳CuO̳4̳-̳y and Pr̳2̳- x̳C̳ex̳CuO̳4̳-̳y. Thermopower measurements were also performed on the samples and show a dramatic change from the underdoped region (x < 0.15) to the overdoped region (x < 0.15). Additionally, the standard Fisher-Fisher-Huse (FFH) vortex glass scaling model has been applied to the magnetoresistance data, as well as a modified scaling model (RRA), and the analysis yields values of the vortex glass melting temperature, T̳g, and critical exponent, v(z- 1). A magnetic field versus temperature (H-T) phase diagram has been constructed for the films with cerium content x >̲ 0.14, displaying the vortex glass melting lines. Magnetoresistance data taken as a function of angle, [theta], is also discussed in the context of the vortex glass scaling mode

Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability

The most successful therapeutic strategies for locally advanced cancers continue to combine decades-old classical radiosensitizing chemotherapies with radiotherapy. Molecular targeted radiosensitizers offer the potential to improve the therapeutic ratio by increasing tumor-specific kill while minimizing drug delivery and toxicity to surrounding normal tissue. Auristatins are a potent class of anti-tubulins that sensitize cells to ionizing radiation damage and are chemically amenable to antibody conjugation. To achieve tumor-selective radiosensitization, we synthesized and tested anti-HER2 antibody-drug conjugates of two auristatin derivatives with ionizing radiation. Monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) were attached to the anti-HER2 antibodies trastuzumab and pertuzumab through a cleavable linker. While MMAE is cell permeable, MMAF has limited cell permeability as free drug resulting in diminished cytotoxicity and radiosensitization. However, when attached to trastuzumab or pertuzumab, MMAF was as efficacious as MMAE in blocking HER2-expressing tumor cells in G2-M. Moreover, MMAF anti-HER2 conjugates selectively killed and radiosensitized HER2-rich tumor cells. Importantly, when conjugated to targeting antibody, MMAF had the advantage of decreased bystander and off-target effects compared with MMAE. In murine xenograft models, MMAF anti-HER2 antibody conjugates had less drug accumulated in the normal tissue surrounding tumors compared with MMAE. Therapeutically, systemically injected MMAF anti-HER2 conjugates combined with focal ionizing radiation increased tumor control and improved survival of mice with HER2-rich tumor xenografts. In summary, our results demonstrate the potential of cell-impermeable radiosensitizing warheads to improve the therapeutic ratio of radiotherapy by leveraging antibody-drug conjugate technology

Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy.

Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic auristatin radiosensitization to stimulate anti-tumor immune responses providing a rationale for clinical translational of auristatin antibody drug conjugates with radio-immunotherapy combinations to improve tumor control