Chemotherapy-induced cardiac toxicity is an undesirable yet very common effect that increases the risk of death and reduce the quality of life of individuals undergoing chemotherapy. However, no feasible methods and techniques are available to monitor and detect the degree of cardiotoxicity at an early stage. Therefore, in this project, we aim to develop a fluorescent nanoprobe to image the toxicity within the cardiac tissue induced by an anticancer drug. We have observed that vascular cell adhesion molecule 1 (VCAM1) protein alone with collagen was overly expressed within the heart, when an animal was treated with doxorubicin (DOX), because of inflammation in the epithelial cells. We hypothesize that developing a VCAM1-targeted peptide-based (VHPKQHRGGSKGC) fluorescent nanoprobe can detect and visualize the affected heart. In this regard, we prepared a poly­(lactic-co-glycolic acid) (PLGA) nanoparticle linked with VCAM1 peptide and rhodamine B (PLGA–VCAM1–RhB). Selective binding and higher accumulation of the PLGA–VCAM1–RhB nanoprobes were detected in DOX-treated human cardiomyocyte cells (HCMs) compared to the untreated cells. For in vivo studies, DOX (5 mg/kg) was injected via the tail vein once in two weeks for 6 weeks (3 injection total). PLGA–VCAM1–RhB and PLGA–RhB were injected via the tail vein after 1 week of the last dose of DOX, and images were taken 4 h after administration. A higher fluorescent signal of PLGA–RhB–VCAM-1 (48.62% ± 12.79%) was observed in DOX-treated animals compared to the untreated control PLGA–RhB (10.61% ± 4.90) within the heart, indicating the specificity and targeting ability of PLGA–VCAM1–RhB to the inflamed tissues. The quantified fluorescence intensity of the homogenized cardiac tissue of PLGA–RhB–VCAM1 showed 156% higher intensity than the healthy control group. We conclude that PLGA–VCAM1–RhB has the potential to bind inflamed cardiac cells, thereby detecting DOX-induced cardiotoxicity and damaged heart at an early stage.

Mechanical cues from the extracellular matrix (ECM) regulate vascular endothelial cell (EC) morphology and function. Since naturally derived ECMs are viscoelastic, cells respond to viscoelastic matrices that exhibit stress relaxation, in which a cell‐applied force results in matrix remodeling. To decouple the effects of stress relaxation rate from substrate stiffness on EC behavior, we engineered elastin‐like protein (ELP) hydrogels in which dynamic covalent chemistry (DCC) was used to crosslink hydrazine‐modified ELP (ELP‐HYD) and aldehyde/benzaldehyde‐modified polyethylene glycol (PEG‐ALD/PEG‐BZA). The reversible DCC crosslinks in ELP‐PEG hydrogels create a matrix with independently tunable stiffness and stress relaxation rate. By formulating fast‐relaxing or slow‐relaxing hydrogels with a range of stiffness (500–3300 Pa), we examined the effect of these mechanical properties on EC spreading, proliferation, vascular sprouting, and vascularization. The results show that both stress relaxation rate and stiffness modulate endothelial spreading on two‐dimensional substrates, on which ECs exhibited greater cell spreading on fast‐relaxing hydrogels up through 3 days, compared with slow‐relaxing hydrogels at the same stiffness. In three‐dimensional hydrogels encapsulating ECs and fibroblasts in coculture, the fast‐relaxing, low‐stiffness hydrogels produced the widest vascular sprouts, a measure of vessel maturity. This finding was validated in a murine subcutaneous implantation model, in which the fast‐relaxing, low‐stiffness hydrogel produced significantly more vascularization compared with the slow‐relaxing, low‐stiffness hydrogel. Together, these results suggest that both stress relaxation rate and stiffness modulate endothelial behavior, and that the fast‐relaxing, low‐stiffness hydrogels supported the highest capillary density in vivo.

No abstract