Platelet-Vesicles-Encapsulated RSL-3 Enable Anti-Angiogenesis and Induce Ferroptosis to Inhibit Pancreatic Cancer Progress

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers. It is characterized by stromal richness, lack of blood supply and special metabolic reprogramming in the tumor microenvironment, which is difficult to treat and easy to metastase. Great efforts have been made to develop new drugs which can pass through the stroma and are more effective than traditional chemotherapeutics, such as ferroptosis inducers–Erastin and RSL-3. As current anti-angiogenic therapy drugs alone are suboptimal for PDAC, novel vascular disruption agents in combination with ferroptosis inducers might provide a possible solution. Here, we designed human platelet vesicles (PVs) to camouflage RSL-3 to enhance drug uptake rate by tumor cells and circulation time in vivo, deteriorating the tumor vessels and resulting in tumor embolism to cut the nutrient supply as well as causing cell death due to excessive lipid peroxidation. The RSL-3@PVs can also cause the classic ferroptosis-related change of mitochondrial morphology, with changes in cellular redox levels. Besides that, RSL-3@PVs has been proved to have great biological safety profile in vitro and in vivo. This study demonstrates the promising potential of integrating PVs and RSL-3 as a combination therapy for improving the outcome of PDAC.

A Machine‐Learning‐Based Bibliometric Analysis of Cell Membrane‐Coated Nanoparticles in Biomedical Applications over the Past Eleven Years

“…[19] Moreover, a PM-coated biomimetic nanocarrier has been proven to possess functions of not only decreasing offtarget effect at the tumor site but also thrombosing to cut off nutrition for tumors. [20,21] Cancer treatment is a major problem that mankind is currently working hard on. It can be seen that in Figure 4B,C, the cancer-related topics of membrane-coated nanoparticles include "breast cancer," "metastasis," "immunotherapy," "chemodynamic therapy," and "tumor."…”

“…[ 19 ] Moreover, a PM‐coated biomimetic nanocarrier has been proven to possess functions of not only decreasing off‐target effect at the tumor site but also thrombosing to cut off nutrition for tumors. [ 20 , 21 ] Cancer treatment is a major problem that mankind is currently working hard on. It can be seen that in Figure 4B,C , the cancer‐related topics of membrane‐coated nanoparticles include “breast cancer,” “metastasis,” “immunotherapy,” “chemodynamic therapy,” and “tumor.” CM has the unreplaceable advantage of serving as the nano‐tumor vaccine that stimulates the body's humoral or cellular immunity more effectively to tumor cells in comparison with traditional anti‐cancer therapies.…”

IDH1 Promotes Foam Cell Formation by Aggravating Macrophage Ferroptosis

“…Recent studies have discovered that Jak2V617F, ALOX5, and NCF2 are involved in the formation of atherosclerosis by regulating macrophage ferroptosis [ 38 , 39 ]. Furthermore, the important role of macrophage-mediated ferroptosis in cancer therapy has also been widely researched [ 40 , 41 ]. In colorectal cancer, there is a crosstalk between ferroptosis and three other programmed cell deaths, including necrosis, autophagy, and apoptosis [ 42 ].…”

The role of platelets in the regulation of tumor growth and metastasis: the mechanisms and targeted therapy

“…For the treatment of pancreatic cancer, platelet vesicles were used to coat RSL‐3, a drug that can pass through the stroma and disrupt tumor angiogenesis. Due to platelet vesicles, the uptake of the drug by tumor cells increased, which enhanced tumor embolism and cell death 199 …”

“…Due to platelet vesicles, the uptake of the drug by tumor cells increased, which enhanced tumor embolism and cell death. 199 The capture of platelets by P-selectin was also explored. For example, nanoparticles coated with a P-selectintargeting peptide (PSN peptide) were constructed, and the core of these nanoparticles was filled with ticagrelor or celecoxib.…”