The Delivery of a Wnt Pathway Inhibitor Toward CSCs Requires Stable Liposome Encapsulation and Delayed Drug Release in Tumor Tissues

Abstract

The Wnt signaling pathway is involved in tumorigenesis and various stages of tumor progression, including the epithelialmesenchymal transition, metastasis, and drug resistance. Many efforts have been made to develop drugs targeting this pathway. CGX1321 is a porcupine inhibitor that can effectively block Wnt ligand synthesis and is currently undergoing clinical trials. However, drugs targeting the Wnt pathway may frequently cause adverse events in normal tissues, such as the intestine and skin. Formulation of the drug inside liposomes could enable preferential drug delivery to solid tumor tissues and limit drug exposure in normal organs. We developed a strategy to stably encapsulate CGX1321 inside liposomes with minimal drug releases in circulation. The liposomal drugs were shown to interfere with the aberrant Wnt signaling specifically in tumor tissues, resulting in focused effects on LGR5 + CSCs (cancer stem cells), while sparing other cells from significant cytotoxicity. We showed it is feasible to use such a CSC elimination approach to treat malignant cancers prone to rapid progression using a LoVo tumor model as well as a GA007 patient derived xenograft (PDX) model. Nano drug delivery systems may be required for precision medicine in cancer therapy.

Construction and analysis of competing endogenous RNA network of MCF‑7 breast cancer cells based on the inhibitory effect of 6‑thioguanine on cell proliferation

“…Many standard clinical drugs, such as cyclophosphamide, capecitabine and doxorubicin, have been determined to have inhibitory effects on breast cancer ( 4 – 7 ). 6-TG has been used as an anticancer and immunosuppressant in medical practice for over 50 years ( 8 ).…”

Recent advances in drug delivery systems for targeting cancer stem cells

“…Similar results were obtained in an orthotropic chemo-resistant breast cancer PDX model in vivo . Table 1 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 summarizes more DDSs and carriers that have been targeted at the CSC signaling pathways.…”

“… Signaling pathway Drug Carrier and feature Cell line Ref. Stemness Napabucasin iRGD peptide-decorated, reduction-sensitive polymersomes Human prostate stem cells, human pancreatic cancer stem cells 48 MAPK U0126 PEG-PLA NPs HepG2, Hep3B, SMMC-7721 49 WNT DOX, iWnt and ATF 24 peptides Dual receptor targeted iWnt-ATF 24 -IONP MDA-MB-231 50 STAT3 Niclosamide Active targeting A15-SLNs OSCC cells 51 WNT CGX1321 Liposome HEK293, LoVo 52 Proteasome BTZ PEG- b -PLA NPs MDA-MB-468, HCC1937 53 PI3K/AKT PEG-coated GNP and cold plasma A549, T98G 54 P53/P21 dependent manner QAuNP H-357-PEMT 55 TGF- β LY364947 and si Plk1 Cationic lipid-assisted polymeric NPs MDA-MB-231 56 PI3K siAKT2 Triblock structured PM based on the combination of PEI with Pluronic® amphiphilic copolymers MCF-7, MDA-MB-231 57 AKT independent pathway CDF Liposome CCL-23, UM-SCC-1 58 NOTCH DAPT MSN-PEI-GA org NPs MDA-MB-231 59 FER FER siRNA LMWP MDA-MB-231 60 ...…”

“… Co-delivered payload Carrier and feature Cell line Ref. Drug against cancer cells Drug against CSCs DOX miR-21i NIR responsive HGNPs MDA-MB-231, MCF-7 30 PTX CUR pH multistage responsive PPBV MCF7 31 DTX 8-HQ HA-MSS MCF7 73 PTX Sali-ABA iTEP NPs 4T1 146 Platinum (IV) si Notch1 MNP Hep3B, SMMC7721 147 DOX and SN38 PEG−DOX/SN38 NPs MCF7 148 DOX ATRT PEG- b -PLA NPs MDA-MB-231 149 DOX SAL cMLV 4T1, MDA-MB-231 150 PTX CYP mPEG- b -PCC- g -DC self-assembled into micelles DU145, PC3, DU145-TXR, PC3-TXR 151 PTX SAL pH-responsive SWCNT-PEG conjugated with CD44 mAbs MDA-MB-231 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 Cisplatin …”

“…The following section will systematically review recent DDS-based therapies against CSCs ( Fig. 2 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ) and their associated specific mechanisms 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ( Figure 3 , Figure 4 , Figure 5 , Figure 6 , Figure 7 ). Furthermore, it will discuss the current prospects and the challenges associated with these targeted therapies.…”