Dual Regioselective Targeting the Same Receptor in Nanoparticle-Mediated Combination Immuno/Chemotherapy for Enhanced
Victoria O Shipunova1,2, Elena N Komedchikova1, Polina A Kotelnikova1
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, Moscow 117997, Russia.
Abstract:
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 nontargeted 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 effective drug concentration in vitro and a significant enhancement of HER2 cancer therapy compared to monotherapy in vivo. Moreover, this therapeutic combination prevented the appearance of secondary tumor nodes. Thus, the suggested synergistic strategy utilizing dual targeting of the same oncomarker could give rise to efficient methods for aggressive tumors treatment.
Insights
This study introduces a novel dual-targeting strategy for HER2-positive cancers, combining chemotherapy and immunotherapy. This approach significantly enhances treatment efficacy and prevents tumor recurrence by targeting multiple sites on the HER2 oncomarker.
Area of Science:
- Oncology
- Nanotechnology
- Immunotherapy
Background:
- Combination cancer theranostics using image-guided targeted delivery of chemotherapeutic agents show promise but face limitations.
- Challenges include a lack of specific molecular targets and the low therapeutic index of conventional chemotherapy drugs.
- Existing approaches have yielded limited success in improving combination cancer therapy outcomes.
Purpose of the Study:
- To demonstrate a synergistic strategy for combination immuno/chemotherapy using dual regioselective targeting of a single oncomarker (HER2).
- To investigate the efficacy of targeting distinct binding sites of HER2 with compounds having different mechanisms of action.
- To develop an efficient method for aggressive HER2-positive tumor treatment.
Main Methods:
- Utilized a PLGA nanoformulation loaded with Nile Red dye and doxorubicin, functionalized with HER2-targeting affibody ZHER2:342.
- Employed a bifunctional immunotoxin, DARP-LoPE, comprising a modified Pseudomonas exotoxin A (LoPE) and a HER2-targeting DARPin9.29.
- Investigated dual targeting of HER2 subdomain III/IV by affibody and subdomain I by DARPin for enhanced therapeutic delivery.
Main Results:
- The dual targeting strategy demonstrated 60-fold specificity for HER2 subdomain III/IV and effective targeting of subdomain I.
- Achieved a 1000-fold decrease in effective drug concentration in vitro and significant enhancement of HER2 cancer therapy in vivo compared to monotherapy.
- Observed prevention of secondary tumor node formation, indicating potent therapeutic synergy.
Conclusions:
- The proposed synergistic strategy utilizing dual targeting of the same oncomarker (HER2) offers a highly effective approach for combination cancer theranostics.
- This method significantly enhances anticancer therapy for HER2-positive cells, overcoming limitations of monotherapy.
- The dual targeting strategy holds potential for developing efficient treatments for aggressive tumors.
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