CD44-targeted vesicles encapsulating granzyme B as artificial killer cells for potent inhibition of human multiple myeloma in mice

Yinan Zhong, Fenghua Meng (Corresponding author), Wen Zhang, Bin Li, Jan C.M. van Hest, Zhiyuan Zhong (Corresponding author)

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

2 Citaten (Scopus)

Samenvatting

Multiple myeloma (MM) is a malignant blood cancer homing in bone marrow that is particularly hard to treat. The effective treatment for MM shall be not only MM-selective but also capable of homing to bone marrow. Herein, we report on hyaluronic acid-directed reduction-responsive chimaeric polymersomes encapsulating a key player in the NK cells, granzyme B (HA-RCP-GrB) as an artificial killer cell for targeted protein therapy of MM. Interestingly, HA-RCP-GrB displayed high MM-targetability and anti-MM activity with a remarkably low IC50 of 8.1 nM toward CD44 overexpressing LP1 human MM cells. The in vivo biodistribution studies using Cy5-labeled cytochrome C as a model protein demonstrated significantly enhanced accumulation of HA-RCP in the subcutaneous LP1 tumor as well as in the bone marrow of orthotopic LP1 MM model compared with the non-targeted RCP counterparts, confirming that HA-RCP possesses MM-selectivity and is able to deliver proteins to the bone marrow. In accordance, HA-RCP-GrB exerted significantly better suppression of subcutaneous LP1 tumor than the non-targeted RCP-GrB. More interestingly, in the orthotopic LP1 MM-bearing mice, HA-RCP-GrB led to significant survival benefits and less body weight loss over PBS and RCP-GrB. μCT analyses, H&E and TRAP staining revealed that mice treated with HA-RCP-GrB had greatly reduced osteolysis and proliferation of atypical plasma cells in the bone marrow. HA-RCP-GrB has emerged as a novel and effective treatment for multiple myeloma.

Originele taal-2Engels
Pagina's (van-tot)421-430
Aantal pagina's10
TijdschriftJournal of Controlled Release
Volume320
Vroegere onlinedatum3 feb 2020
DOI's
StatusGepubliceerd - 10 apr 2020

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