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Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles
Eric Voltà-Durán1, Naroa Serna1, Laura Sánchez-García1
1Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Bellaterra, 08193 Barcelona, Spain.
Abstract:
The possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities would open a wide spectrum of opportunities in nanomedical oncology. This principle has been explored here by using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respectively have been chemically coupled. The resulting multifunctional hybrid nanoconjugates, with a hydrodynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed here is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs.
Insights
This study explores combining targeted nanoparticles with cancer drugs for enhanced oncology treatments. These hybrid nanoconjugates show promise for overcoming drug resistance and improving cancer therapy effectiveness.
Area of Science:
- Nanomedical Oncology
- Drug Delivery Systems
- Cancer Therapeutics
Background:
- Combining targeted cytotoxic nanoparticles with conventional anticancer drugs into single entities offers significant potential in nanomedical oncology.
- Developing multifunctional hybrid nanoconjugates is crucial for advancing cancer treatment strategies.
- Addressing challenges in cancer therapy, such as acquired drug resistance, necessitates innovative approaches.
Purpose of the Study:
- To explore the principle of conjugating tumor-targeted cytotoxic nanoparticles with conventional antitumoral drugs.
- To create novel multifunctional hybrid nanoconjugates for potential nanomedical oncology applications.
- To evaluate the feasibility and promise of combining different therapeutic agents within single nanocarriers.
Main Methods:
- Utilized CXCR4-targeted self-assembling protein nanoparticles derived from Pseudomonas aeruginosa exotoxin A and Corynebacterium diphtheriae diphtheria toxin.
- Chemically coupled oligo-floxuridine and monomethyl auristatin E to the respective protein nanoparticles.
- Characterized the resulting hybrid nanoconjugates for stability, size (hydrodynamic size ~50 nm), and cellular internalization.
Main Results:
- Successfully synthesized stable, multifunctional hybrid nanoconjugates with a hydrodynamic size of approximately 50 nm.
- Demonstrated that these nanoconjugates internalize target cells and exhibit biological impact.
- Observed that chemical conjugation reduced the cytotoxic activity of the protein component.
Conclusions:
- The concept of combining targeted nanoparticles with cytotoxic drugs in single entities is feasible and highly promising for nanomedical oncology.
- These hybrid nanoconjugates offer a viable strategy for multi-drug cancer treatments, potentially increasing effectiveness.
- The approach holds significant promise for treating cancers that have developed resistance to conventional therapies.
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