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Anticancer Efficacy of Photodynamic Therapy with Lung Cancer-Targeted Nanoparticles
Published on: December 1, 2016
In Vitro and In Vivo Evaluation of Alectinib-Loaded Dendrimer Nanoparticles as a Drug Delivery System for Non-Small
Mahmood R Atta1, Israa Al-Ani1, Ibrahim Aldeeb2
1Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Pharmacological and Diagnostic Research Center (PDRC), Al-Ahliyya Amman University, Amman 19328, Jordan.
Abstract:
Background/Objectives: Alectinib, a second-generation tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer (NSCLC), exhibits suboptimal oral bioavailability, primarily attributable to its inherently low aqueous solubility and limited dissolution kinetics. This study aimed to enhance Alectinib's solubility and therapeutic efficacy by formulating a G4-NH2-PAMAM dendrimer complex. Methods: The complex was prepared using the organic solvent evaporation method and characterized by DSC, FTIR, dynamic light scattering (DLS), and zeta potential measurements. A validated high-performance liquid chromatography (HPLC) method quantified the Alectinib. In vitro drug release studies compared free Alectinib with the G4-NH2-PAMAM dendrimer complex. Cytotoxicity against NSCLC cell line A549 was assessed using MTT assays, clonogenic assay, and scratch-wound assay. Xenograft effect was investigated in the H460 lung cell line. Pharmacokinetic parameters were evaluated in rats using LC-MS/MS. Results: Alectinib exhibited an encapsulation efficiency of 59 ± 5%. In vitro release studies demonstrated sustained drug release at pH 6.8 and faster degradation at pH 2.5. Anticancer activity in vitro showed comparable efficacy to free Alectinib, with 98% migration inhibition. In vivo tumor suppression studies revealed near-complete tumor regression (~100%) after 17 days of treatment, compared to 75% with free Alectinib. Pharmacokinetic analysis indicated enhanced absorption (shorter Tmax), prolonged systemic circulation (longer half-life), and higher bioavailability (increased AUC) for the dendrimer-complexed drug. Conclusions: These findings suggest that the G4-NH2-PAMAM dendrimer system significantly improves Alectinib's pharmacokinetics and therapeutic potential, making it a promising approach for NSCLC treatment.
Insights
Formulating Alectinib with G4-NH2-PAMAM dendrimers significantly enhances its oral bioavailability and therapeutic efficacy for non-small-cell lung cancer (NSCLC) treatment. This dendrimer complex improves drug absorption, circulation, and tumor suppression, offering a promising new strategy for NSCLC therapy.
Area of Science:
- Nanotechnology
- Pharmaceutical Sciences
- Oncology
Background:
- Alectinib, a tyrosine kinase inhibitor for non-small-cell lung cancer (NSCLC), has poor oral bioavailability due to low solubility and dissolution.
- Developing strategies to improve Alectinib's pharmacokinetic profile is crucial for enhancing its therapeutic potential.
Purpose of the Study:
- To enhance the solubility and therapeutic efficacy of Alectinib by formulating a G4-NH2-PAMAM dendrimer complex.
- To evaluate the in vitro and in vivo performance of the Alectinib-dendrimer formulation for NSCLC treatment.
Main Methods:
- Preparation of the Alectinib-G4-NH2-PAMAM dendrimer complex using organic solvent evaporation.
- Characterization via DSC, FTIR, DLS, and zeta potential; quantification by HPLC.
- In vitro drug release, cytotoxicity assays (MTT, clonogenic, scratch-wound), in vivo xenograft studies, and pharmacokinetic evaluation in rats (LC-MS/MS).
Main Results:
- Encapsulation efficiency of 59 ± 5%; sustained in vitro drug release at pH 6.8.
- Comparable in vitro anticancer efficacy with 98% migration inhibition; near-complete tumor regression (~100%) in vivo.
- Improved pharmacokinetics: enhanced absorption, prolonged circulation, and increased bioavailability (AUC) compared to free Alectinib.
Conclusions:
- G4-NH2-PAMAM dendrimer formulation significantly enhances Alectinib's pharmacokinetic properties and therapeutic potential.
- This dendrimer-based approach represents a promising strategy for improving the treatment of non-small-cell lung cancer.
