BODIPYs are photosensitizers activatable by light to generate highly reactive singlet oxygen (O) from molecular oxygen, leading to tissue damage in the photoirradiated region. Despite their extraordinary photophysical characteristics, they are not featured in clinical photodynamic therapy. This review discusses the recent advances in the design and/or modifications of BODIPYs since 2013, to improve their potential in photodynamic cancer therapy and related areas.
For the purpose of this review, active targeting in cancer research encompasses strategies wherein a ligand for a cell surface receptor expressed on tumor cells is used to deliver a cytotoxic or imaging cargo. This area of research is more than two decades old, but in those 20 and more years, how many receptors have been studied extensively? What kinds of the ligands are used for active targeting? Are they mostly naturally occurring molecules such as folic acid, or synthetic substances developed in campaigns for medicinal chemistry efforts? This review outlines the most important receptor or ligand combinations that have been used in active targeting to answer these questions, and therefore to address the most important one of all: is research in active targeting affording diminishing returns, or is this an area for which the potential far exceeds progress made so far?
The chick embryo chorioallantoic membrane (CAM) is a preclinical model widely used for
vascular and anti-vascular effects of therapeutic agents in vivo. In this
study, we examine the suitability of CAM as a predictive model for acute toxicology
studies of drugs by comparing it to conventional mouse and rat models for 10 FDA-approved
anticancer drugs (paclitaxel, carmustine, camptothecin, cyclophosphamide, vincristine,
cisplatin, aloin, mitomycin C, actinomycin-D, melphalan). Suitable formulations for
intravenous administration were determined before the average of median lethal dose
(LD50) and median survival dose (SD50) in the CAM were measured
and calculated for these drugs. The resultant ideal LD50 values were correlated
to those reported in the literature using Pearson’s correlation test for both intravenous
and intraperitoneal routes of injection in rodents. Our results showed moderate
correlations (r2=0.42 − 0.68, P<0.005–0.05) between the
ideal LD50 values obtained using the CAM model with LD50 values from
mice and rats models for both intravenous and intraperitoneal administrations, suggesting
that the chick embryo may be a suitable alternative model for acute drug toxicity
screening before embarking on full toxicological investigations in rodents in development
of anticancer drugs.
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 1O2 production conjugated to this structure
gives 1-PDT for photodynamic therapy. Isomeric 2-PDT does 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-PDT where 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-PDT on TrkC+ tumors. In contrast, 1-PDT caused dramatic TrkC+ tumor volume reduction (96%
from initial) relative to the TrkC– tumors or 2-PDT in 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.
Nanosized constructs are widely applied to address the common drawbacks of conventional cancer therapy, such as a nonspecific biodistribution, toxicity and targeting. Nevertheless, there are several challenges in transporting sufficient drugs to the tumor using these nanoconstructs, which are discussed in this review. Additionally, the current opportunities that improve the biodistribution of nanoconstructs, tumor penetration and drug accumulation are elaborated. The distinct features of currently available strategies do not adequately fit the classical passive and active targeting categories; therefore, in this review, they are regrouped into autonomous and nonautonomous drug delivery systems. Autonomous systems are defined as self-directed systems that can enhance nanoparticle retention and distribution in solid tumors without the need to align with the blood flow direction, while non-autonomous systems primarily rely on the blood flow direction, longevity in the circulation and specific affinity to the target cells. Moreover, the effectiveness of the existing delivery systems could be further improved through the correct choice of route of administration. The role of the route of administration in improving these drug delivery methods and some recent examples of locoregional cancer therapy are discussed. These findings could stimulate improvements in the delivery of multifunctional nanoconstructs, which could facilitate successful cancer treatments.
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.
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