Liposome-Encapsulated Bacillus Calmette–Guérin Cell Wall Skeleton Enhances Antitumor Efficiency for Bladder Cancer In Vitro and In Vivo via Induction of AMP-Activated Protein Kinase

Abstract

The Mycobacterium Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate non-infectious immunotherapeutic drug and an alternative to live BCG for use against urothelial carcinoma. However, its application in anticancer therapy is limited, as BCG-CWS tends to aggregate in both aqueous and non-aqueous solvents. To improve the internalization of BCG-CWS into bladder cancer cells without aggregation, BCG-CWS was nanoparticulated at a 180 nm size in methylene chloride and subsequently encapsulated with conventional liposomes (CWS-Nano-CL) using an emulsified lipid (LEEL) method. In vitro cell proliferation assays showed that CWS-Nano-CL was more effective at suppressing bladder cancer cell growth compared to nonenveloped BCG-CWS. In an orthotopic implantation model of luciferase-tagged MBT2 bladder cancer cells, encapsulated BCG-CWS nanoparticles could enhance the delivery of BCG-CWS into the bladder and suppress tumor growth. Treatment with CWS-Nano-CL induced the inhibition of the mammalian target of rapamycin (mTOR) pathway and the activation of AMP-activated protein kinase (AMPK) phosphorylation, leading to apoptosis, both in vitro and in vivo. Furthermore, the antitumor activity of CWS-Nano-CL was mediated predominantly by reactive oxygen species (ROS) generation and AMPK activation, which induced endoplasmic reticulum (ER) stress, followed by c-Jun N-terminal kinase (JNK) signaling-mediated apoptosis. Therefore, our data suggest that the intravesical instillation of liposome-encapsulated BCG-CWS nanoparticles can facilitate BCG-CW cellular endocytosis and provide a promising drug-delivery system as a therapeutic strategy for BCG-mediated bladder cancer treatment.

Physical & Chemical Microwave Ablation (MWA) Enabled by Nonionic MWA Nanosensitizers Repress Incomplete MWA-Arised Liver Tumor Recurrence

“…It determines that more DOX in EF-DOX-Lips is delivered into cells after 1 h, especially after MWA is added, since MWA-induced heat also enhances permeability for drug delivery akin to other heat-enhanced permeability. 40,41 After 3 h, LCSM images and FCM results show that MWA triggers an abundant DOX release and the accumulation from EF-DOX-Lips in nuclei (Figures 4f,g and S3a) and subsequently induces the highest cytotoxicity (91.9% vs 60−75%) (Figures 4h,i and S3b). A prolonged incubation time induces more deaths (Figure 4j).…”

Low-dose versus standard-dose bacille Calmette–Guérin for non-muscle-invasive bladder cancer: Systematic review and meta-analysis of randomized controlled trials

“…Fourth, studies on increasing the invasion of BCG were conducted. Drug delivery systems such as nanocarriers or liposomes could promote endocytosis and the antitumor effects of BCG [ 32 ]. In the case of these upgraded tools, low-dose BCG can be used to reduce adverse effects.…”

A Review on Cancer Immunotherapy and Applications of Nanotechnology to Chemoimmunotherapy of Different Cancers

“…In another study, BCG-CWS nanoparticles were encapsulated in liposomes in order to reduce the side effects of BCG treatment. As a result of this study, increased antitumor activity was also shown with the induction of autophagy and ROS production [ 122 ].…”