Photothermic therapy with cuttlefish ink-based nanoparticles in combination with anti-OX40 mAb achieve remission of triple-negative breast cancer.

Immunostimulatory monoclonal antibodies (IS-mAb) have been proven to enhance the therapeutic effectiveness of various anticancer therapy. In the present investigation, we launched a separate combinational therapy for the treatment of triple-negative breast cancer (TNBC) using cuttlefish ink-based nanoparticles (CINPs) for photothermal therapy (PTT) and anti-OX40 antibody. Our goal was to increase the therapeutic response to the disease. CINPs were characterized by their physicochemical properties, which revealed that they had a hydrodynamic diameter ranging from 128 to 148 nm, a negative surface charge, and a high photothermal conversion efficiency under both in vitro and in vivo settings. In TNBC model, we evaluated the therapeutic effectiveness of the following groups: CINP-PTT + anti-OX40 Ab (G1), CINPs-PTT (G2), CINPs + anti-OX40 Ab (G3), anti-OX40 (G4) or PBS (G5). In each case, we assessed the efficacy of these groups against one another. The intratumor administration of all of the substances and therapies was performed. CINP-PTT + anti-OX40 Ab and CINP + anti-OX40 Ab (particularly CINP-PTT + anti-OX40 Ab) induced significant tumor regression in treated (breast) and non-treated (flank) tumor, and completely inhibited lung metastasis, thereby inducing a higher survival rate in mice in comparison to CINP-PTT, anti-OX40 Ab, or PBS. This was the case because in CINPs-treated tumors, particularly those treated with CINPs-PTT, intratumoral injection of CINPs increased the frequency of OX40, CD8 double-positive T cells. CINPs improved the conversion of the macrophage phenotype from M2 to M1 in vitro, which is significant from an immunological point of view. In addition, anti-OX40 Ab combined with CINPs or, more specifically, CINPs-PPT produced a larger frequency of preexisting and newly formed tumor-specific CD8 T cells, as well as an enhanced frequency of CD8 T cells infiltrating non-treated tumors, in comparison to respective monotherapies. When the data were taken into consideration as a whole, it seemed that CINPs-based PTT may effectively enhance the antitumor response effectiveness of anti-OX40 Ab.

Substitution of lysine for isoleucine at the center of the nonpolar face of the antimicrobial peptide, piscidin-1, leads to an increase in the rapidity of bactericidal activity and a reduction in toxicity.

Purpose: Piscidin-1 is an effective antimicrobial peptide (AMP) against a variety of microbes. However, its toxicity has been reported as a limitation for its potential therapeutic applications. The toxicity of piscidin-1 may be related to the long nonpolar face of this AMP. Here, we investigated different piscidin-1 analogs to reach a peptide with the reduced toxicity. Material and methods: In vitro and in vivo antibacterial activity and toxicity of piscidin-1 analogs generated by replacement of isoleucine at the border (I9) or the center (I16) of the nonpolar face of piscidin-1 by alanine or lysine were investigated. Results: The results indicated that among all peptides, piscidin-1 with the highest HPLC retention time (RT) and I16K-piscidin-1 with the lowest RT had the highest and lowest cytotoxicity, respectively. Although I16K-piscidin-1 possessed the same MIC value as the parent peptide (piscidin-1) and other analogs, I16K-piscidin-1 exhibited a higher rapidity of bactericidal action at 5×MIC. The ß-galactosidase leakage and propidium iodide staining assays indicated a higher pore-forming capacity of I16K-piscidin-1 relative to the parent peptide (piscidin-1). Taken together, RT is suggested to have a direct association with the toxicity and an inverse association with the rapidity of bactericidal action and pore-forming capacity. After infection of mice with clinical colistin-resistant Acinetobacter baumannii or clinical methicillin-resistant Staphylococcus aureus strains, treatment with I16K-piscidin-1, but not piscidin-1 and other analogs, resulted in a significantly stronger bactericidal potency. Furthermore, I16K-piscidin-1 exhibited the lowest in vivo toxicity.  Conclusion: Overall, in vitro and in vivo comparison of piscidin-1 and its analogs together documented that replacement of isoleucine at the center of the nonpolar face of piscidin-1(I16) by lysine leads to not only a decrease in toxicity potential but also an increase in bactericidal potential.