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Background: Stattic offers a unique inhibitory effect on the STAT3 signaling pathway, a crucial mechanism in the progression of metastatic cancer. However, the development of Stattic has been impeded by its hydrophobicity and lack of specificity. To overcome these limitations, encapsulation of Stattic with polymeric micelles was previously attempted, which led to a significant increase in the potency of Stattic on breast cancer cell lines. The presence of albumin was believed to contribute to such enhancement, as the protein corona layer formation helps retain the micellar structure before eventual uptake by the cells. Moreover, a previous study had reported the unique affinity of Stattic towards albumin molecule. Objective: This study aimed to explore the integration of Stattic in albumin-based nanoparticles and to assess the in vitro effects. Methods: Albumin/Stattic nanoparticles were prepared by crosslinking with glutaraldehyde. Results: The yielded nanoparticles were 150.0 ± 6.6 nm in size, with 53% entrapment efficiency. The cumulative release of Stattic in a tumoric acidic environment (pH 5.3; 59%) was 2.6-fold more than neutral environment (pH 7.4; 23%). In blood plasma, 7% cumulative release was observed. The mathematical modeling of the release kinetics revealed that the albumin/Stattic nanoparticles in phosphate buffer saline and plasma followed Korsmeyer-Peppas and Higuchi models, respectively. Among the two cell lines tested, metastatic MDA-MB-231 cells were more sensitive to entrapment of Stattic with albumin nanoparticles, as the IC50 value decreased by 2.5-fold compared to free Stattic. Conclusion: This study reports the formation of low immunogenic and cost-efficient albumin nanoparticles to improve the delivery of Stattic.

Photosensitizing nanogels were obtained through a surfactant-free single-step protocol by using a porphyrin-based cross-linker for stabilizing self-assembled nanosized aggregates of thermoresponsive copolymers. Nanogels with varying amounts of porphyrin retained the singlet oxygen generation ability of the porphyrin core and were also capable of inducing temperature increase upon irradiation at 635 nm. Photoinduced killing efficiency was tested against three cell lines: human breast adenocarcinoma (MDA-MB-231 and MCF7) and pancreatic adenocarcinoma (AsPC-1) cells, and a predominant photodynamic mechanism at 450 nm and a mixed photodynamic and photothermal effect at 635 nm was observed. This innovative access to photosensitizing nanogels is a proof of concept, and opens new perspectives toward the preparation of optimized nanophotosensitizers.

We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PGpossessed high near-infrared (NIR) light absorptivity (λmax= 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PGaccumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG(2 mg of Pc 1equivalent/kg) induced a greater tumor volume reduction (−74 ± 5%) when compared to high dose ZnPc(8 mg/kg, −50 ± 12%). At higher treatment doses (8 mg of Pc 1equivalent/kg), 1-PGreduced tumor volume maximally (−91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG(both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PGas a useful photosensitizer candidate for clinical PDT.

This contribution features a small molecule that binds TrkC (tropomyosin receptor kinase C) receptor that tends to be overexpressed in metastatic breast cancer cells but not in other breast cancer cells. A sensitizer for 1O2production conjugated to this structure gives 1-PDTfor photodynamic therapy. Isomeric 2-PDTdoes not bind TrkC and was used as a control throughout; similarly, TrkC– cancer cells were used to calibrate enhanced killing of TrkC+ cells. Ex vivo, 1- and 2-PDTwhere only cytotoxic when illuminated, and 1-PDT, gave higher cell death for TrkC+ breast cancer cells. A 1 h administration-to-illumination delay gave optimal TrkC+/TrkC–-photocytotoxicity, and distribution studies showed the same delay was appropriate in vivo. In Balb/c mice, a maximum tolerated dose of 20 mg/kg was determined for 1-PDT. 1- and 2-PDT(single, 2 or 10 mg/kg doses and one illumination, throughout) had similar effects on implanted TrkC– tumors, and like those of 2-PDTon TrkC+ tumors. In contrast, 1-PDTcaused dramatic TrkC+ tumor volume reduction (96% from initial) relative to the TrkC– tumors or 2-PDTin TrkC+ models. Moreover, 71% of the mice treated with 10 mg/kg 1-PDT (n= 7) showed full tumor remission and survived until 90 days with no metastasis to key organs.

This study aims to improve the photodynamic properties and biological effectiveness of 151-hydroxypurpurin-7-lactone dimethyl ester (G2), a semisynthetic photosensitizer, for the PDT treatment of cancer. The strategy we undertook was by conjugating G2 with aspartic acid and lysine amino acid moieties. The photophysical properties, singlet oxygen generation, distribution coefficiency (Log Din octanol/PBS pH 7.4), and photostability of these analogues and their in vitrobioactivities such as cellular uptake, intracellular localization, and photoinduced cytotoxicity were evaluated. In addition, selected analogues were also investigated for their PDT-induced vasculature occlusion in the chick chorioallantoic membrane model and for their antitumor efficacies in Balb/C mice bearing 4T1 mouse mammary tumor. From the study, conjugation with aspartic acid improved the aqueous solubility of G2 without affecting its photophysical characteristics. G2-Asp showed similar in vitroand in vivoantitumor efficacies compared to the parent compound. Given the hydrophilic nature of G2-Asp, the photosensitizer is a pharmaceutically advantageous candidate as it can be formulated easily for systemic administration and has reduced risk of aggregation in vascular system.

Stattic is a signaling pathway inhibitor that could potentially impede the progression of tumor metastasis. However, the pharmaceutical applications of Stattic are hampered by its poor water solubility. In this study, we explored the integration of Stattic within amphiphilic pendant-dendron copolymeric (P71D3) micelles to improve its water solubility and delivery towards tumor cells. The P71D3/Stattic micelles with a 1:1.2 (P71D3:Stattic) ratio optimized for subsequent studies were 164 nm in diameter with a drug loading percentage of 52% w/w. These P71D3/Stattic micelles demonstrated a higher drug release (32%) in acidic tumor conditions compared to neutral physiological conditions (14%). However, rapid and high Stattic release was observed when dialyzed against a simulated plasma solution containing 4% albumin. Interestingly, when the same Stattic-loaded micelles and 4% albumin solution were in direct contact, the albumin molecules bound to the surface of the micelles, forming a protein corona. P71D3/Stattic micelles were found to be 30- to 90-fold more potent and to decrease the effective antimotility concentration by 3- to 6-fold compared to free Stattic in metastatic human and murine mammary cancer cells. The P71D3/Stattic micelles effectively enhanced the potency of the drug as determined from the in vitrostudies, suggesting the use of P71D3/Stattic micelles as a promising antimetastatic agent worthy of further study.

Despite the extensive work on anticancer drug discovery, the number of potent lead compounds that enter the preclinical and clinical trials thus far is still low due to the poor selectivity and understanding in pharmacodynamics. In view of the homology between zebrafish embryogenesis and carcinogenesis in human, zebrafish embryos can be used in the screening platform to elucidate the molecular targets of potential anticancer compounds. In the present study, the possible targets modulating the potential anticancer effects of selected brown seaweed-derived compounds (ie alginate, fucoidan, phloroglucinol, fucosterol, and fucoxanthin) were examined. Teratogenic effects induced by the compounds were observed after 72 hours post-fertilization. Fucoidan, phloroglucinol, and fucosterol were observed to significantly reduce the pigmentation of the zebrafish in a dose-dependent manner at low concentrations (fucoidan, <60 µg/mL; phloroglucinol, <10 µg/mL; fucosterol, <3 µg/mL). On the other hand, embryos treated with fucoxanthin at 200 µg/mL and 300 µg/mL exhibited either phenotypes of curved trunk or bent tail. Further validation work using dual antiplatelet therapy (DAPT) and dorsomorphin as positive controls suggest that fucoxanthin might target the Notch and bone morphogenetic protein (BMP) pathways, respectively. Findings from this exploratory study henceforth have demonstrated the utility of zebrafish embryo to accelerate the discovery of potential compounds for targeted anticancer therapy.