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Trastuzumab Targeted Neratinib Loaded Poly-Amidoamine Dendrimer Nanocapsules for Breast Cancer Therapy
Fadilah Sfouq Aleanizy1, Fulwah Yahya Alqahtani1, Sara Seto1
1Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Background:
Human epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy.
Methods:
TZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake.
Results:
The G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer.
Conclusion:
In the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.
Insights
Trastuzumab-grafted dendrimers loaded with neratinib show enhanced delivery and higher anti-cancer activity against HER2-positive breast cancer cells. This dual-targeted therapy offers improved efficacy and potential to overcome drug resistance.
Area of Science:
- Nanotechnology
- Oncology
- Drug Delivery
Background:
- HER2-positive breast cancer affects 25% of cases, with trastuzumab (TZ) as a first-line targeted therapy.
- Neratinib, an irreversible HER2 inhibitor, is approved as adjuvant therapy with TZ.
- Developing novel drug delivery systems is crucial for improving breast cancer treatment efficacy.
Purpose of the Study:
- To formulate trastuzumab-grafted dendrimers loaded with neratinib for dual targeted therapy.
- To evaluate the efficacy of this novel formulation in HER2-positive breast cancer models.
- To assess the potential of this approach in overcoming therapeutic resistance.
Main Methods:
- Conjugation of trastuzumab (TZ) onto dendrimer surfaces using MAL-PEG-NHS crosslinker.
- Characterization of dendrimer zeta potential and in vitro neratinib release kinetics.
- Quantification of cellular uptake in SKBR-3 cells using fluorescently labeled dendrimers.
Main Results:
- G4 PAMAM dendrimers successfully encapsulated neratinib, demonstrating a sustained release profile.
- TZ-targeted dendrimers loaded with neratinib exhibited superior selectivity and antiproliferative activity against SKBR-3 cells compared to neratinib alone.
- Enhanced cellular uptake was observed for trastuzumab-conjugated dendrimers.
Conclusions:
- Neratinib-loaded dendrimers, both plain and trastuzumab-grafted, were successfully prepared.
- Trastuzumab conjugation significantly enhanced cellular uptake and cytotoxic effects compared to plain dendrimers.
- TZ-conjugated dendrimers show promise as targeted carriers for cytotoxic drugs like neratinib in breast cancer therapy.
