An Evaluation of CXCR4 Targeting with PAMAM Dendrimer Conjugates for Oncologic Applications
Wojciech G Lesniak1, Babak Behnam Azad1, Samit Chatterjee1
1Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287, USA.
Abstract:
The chemokine receptor 4 (CXCR4) is a promising diagnostic and therapeutic target for the management of various cancers. CXCR4 has been utilized in immunotherapy, targeted drug delivery, and endoradiotherapy. Poly(amidoamine) [PAMAM] dendrimers are well-defined polymers with unique properties that have been used in the fabrication of nanomaterials for several biomedical applications. Here, we describe the formulation and pharmacokinetics of generation-5 CXCR4-targeted PAMAM (G5-X4) dendrimers. G5-X4 demonstrated an IC50 of 0.95 nM to CXCR4 against CXCL12-Red in CHO-SNAP-CXCR4 cells. Single-photon computed tomography/computed tomography imaging and biodistribution studies of 111In-labeled G5-X4 showed enhanced uptake in subcutaneous U87 glioblastoma tumors stably expressing CXCR4 with 8.2 ± 2.1, 8.4 ± 0.5, 11.5 ± 0.9, 10.4 ± 2.6, and 8.8 ± 0.5% injected dose per gram of tissue at 1, 3, 24, 48, and 120 h after injection, respectively. Specific accumulation of [111In]G5-X4 in CXCR4-positive tumors was inhibited by the peptidomimetic CXCR4 inhibitor, POL3026. Our results demonstrate that while CXCR4 targeting is beneficial for tumor accumulation at early time points, differences in tumor uptake are diminished over time as passive accumulation takes place. This study further confirms the applicability of PAMAM dendrimers for imaging and therapeutic applications. It also emphasizes careful consideration of image acquisition and/or treatment times when designing dendritic nanoplatforms for tumor targeting.
Insights
This study developed generation-5 CXCR4-targeted PAMAM (G5-X4) dendrimers for cancer imaging. G5-X4 showed high affinity for CXCR4 and enhanced tumor uptake, confirming PAMAM dendrimers
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Chemokine receptor 4 (CXCR4) is a key target in cancer diagnostics and therapeutics.
- Poly(amidoamine) (PAMAM) dendrimers offer unique properties for biomedical nanomaterial fabrication.
Purpose of the Study:
- To formulate and characterize generation-5 CXCR4-targeted PAMAM (G5-X4) dendrimers.
- To evaluate the pharmacokinetic and tumor-targeting capabilities of G5-X4 for cancer imaging.
Main Methods:
- Formulation of G5-X4 dendrimers and assessment of their binding affinity to CXCR4.
- In vivo imaging and biodistribution studies using 111In-labeled G5-X4 in glioblastoma models.
- Inhibition studies using a CXCR4 antagonist (POL3026) to confirm target specificity.
Main Results:
- G5-X4 demonstrated high binding affinity to CXCR4 (IC50 = 0.95 nM).
- Significant accumulation of 111In-labeled G5-X4 was observed in CXCR4-positive glioblastoma tumors.
- Tumor uptake specificity was confirmed by inhibition studies, though diminished over time due to passive accumulation.
Conclusions:
- CXCR4-targeted PAMAM dendrimers show promise for cancer imaging and therapy.
- Optimal imaging and treatment timing are crucial for maximizing the benefits of dendritic nanoplatforms.
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