Dual Regioselective Targeting the Same Receptor in Nanoparticle-Mediated Combination Immuno/Chemotherapy for Enhanced Image-Guided Cancer Treatment

When combined with immunotherapy, image-guided targeted delivery of chemotherapeutic agents is a promising direction for combination cancer theranostics, but this approach has so far produced only limited success due to a lack of molecular targets on the cell surface and low therapeutic index of con...

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Bibliographic Details
Published in:ACS nano 2020-10, Vol.14 (10), p.12781-12795
Main Authors: Shipunova, Victoria O, Komedchikova, Elena N, Kotelnikova, Polina A, Zelepukin, Ivan V, Schulga, Alexey A, Proshkina, Galina M, Shramova, Elena I, Kutscher, Hilliard L, Telegin, Georgij B, Kabashin, Andrei V, Prasad, Paras N, Deyev, Sergey M
Format: Article
Language:English
Subjects:
Condensed Matter
Materials Science
Optics
Physics
Plasma Physics
Online Access:Get full text
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Summary:When combined with immunotherapy, image-guided targeted delivery of chemotherapeutic agents is a promising direction for combination cancer theranostics, but this approach has so far produced only limited success due to a lack of molecular targets on the cell surface and low therapeutic index of conventional chemotherapy drugs. Here, we demonstrate a synergistic strategy of combination immuno/chemotherapy in conditions of dual regioselective targeting, implying vectoring of two distinct binding sites of a single oncomarker (here, HER2) with theranostic compounds having a different mechanism of action. We use: (i) PLGA nanoformulation, loaded with an imaging diagnostic fluorescent dye (Nile Red) and a chemotherapeutic drug (doxorubicin), and functionalized with affibody ZHER2:342 (8 kDa); (ii) bifunctional genetically engineered DARP-LoPE (42 kDa) immunotoxin comprising of a low-immunogenic modification of therapeutic Pseudomonas exotoxin A (LoPE) and a scaffold targeting protein, DARPin9.29 (14 kDa). According to the proposed strategy, the first chemotherapeutic nanoagent is targeted by the affibody to subdomain III and IV of HER2 with 60-fold specificity compared with non-targeted particles, while the second immunotoxin is effectively targeted by DARPin molecule to subdomain I of HER2. We demonstrate that this dual targeting strategy can enhance anticancer therapy of HER2-positive cells with a very strong synergy, which made possible 1000-fold decrease of
ISSN:1936-0851
DOI:10.1021/acsnano.0c03421