ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression
Linxi Zhu1, Qingxin Mu1, Jesse Yu1
1Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
Abstract:
Despite the availability of molecularly targeted treatments such as antibodies and small molecules for human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and programmed death-ligand 1 (PD-L1), limited treatment options are available for advanced metastatic breast cancer (MBC), which constitutes ~90% mortality. Many of these monotherapies often lead to drug resistance. Novel MBC-targeted drug-combination therapeutic approaches that may reduce resistance are urgently needed. We investigated intercellular adhesion molecule-1 (ICAM-1), which is abundant in MBC, as a potential target to co-localize two current drug combinations, gemcitabine (G) and paclitaxel (T), assembled in a novel drug-combination nanoparticle (GT DcNP) form. With an ICAM-1-binding peptide (referred to as LFA1-P) coated on GT DcNPs, we evaluated the role of the LFA1-P density in breast cancer cell localization in vitro and in vivo. We found that 1-2% LFA1-P peptide incorporated on GT DcNPs provided optimal cancer cell binding in vitro with ~4× enhancement compared to non-peptide GT DcNPs. The in vivo probing of GT DcNPs labeled with a near-infrared marker, indocyanine green, in mice by bio-imaging and G and T analyses indicated LFA1-P enhanced drug and GT DcNP localization in breast cancer cells. The target/healthy tissue (lung/gastrointestinal (GI)) ratio of particles increased by ~60× compared to the non-ligand control. Collectively, these data indicated that LFA1 on GT DcNPs may provide ICAM-1-targeted G and T drug combination delivery to advancing MBC cells found in lung tissues. As ICAM-1 is generally expressed even in breast cancers that are triple-negative phenotypes, which are unresponsive to inhibitors of nuclear receptors or HER2/estrogen receptor (ER) agents, ICAM-1-targeted LFA1-P-coated GT DcNPs should be considered for clinical development to improve therapeutic outcomes of MBCs.
Insights
Targeting intercellular adhesion molecule-1 (ICAM-1) with novel nanoparticles carrying gemcitabine and paclitaxel enhances drug delivery to metastatic breast cancer cells, potentially overcoming resistance and improving outcomes.
Area of Science:
- Oncology
- Nanomedicine
- Drug Delivery
Background:
- Advanced metastatic breast cancer (MBC) has limited treatment options and high mortality.
- Current therapies like HER2, HR, and PD-L1 inhibitors often face drug resistance.
- Novel combination therapies targeting MBC are urgently needed to improve patient outcomes.
Purpose of the Study:
- To investigate intercellular adhesion molecule-1 (ICAM-1) as a target for delivering gemcitabine (G) and paclitaxel (T) combination therapy.
- To develop and evaluate ICAM-1-binding peptide (LFA1-P) coated nanoparticles (GT DcNPs) for enhanced MBC cell localization.
- To determine the optimal LFA1-P density for effective drug delivery in vitro and in vivo.
Main Methods:
- Developed novel drug-combination nanoparticles (GT DcNPs) encapsulating gemcitabine and paclitaxel.
- Coated GT DcNPs with an ICAM-1-binding peptide (LFA1-P) at varying densities.
- Evaluated in vitro cancer cell binding and in vivo biodistribution and drug localization in mice using bio-imaging.
- Analyzed drug concentrations in target and healthy tissues.
Main Results:
- Optimal cancer cell binding was achieved with 1-2% LFA1-P density on GT DcNPs, showing a ~4x enhancement compared to non-peptide nanoparticles.
- In vivo studies demonstrated that LFA1-P enhanced the localization of GT DcNPs and drugs in breast cancer cells.
- The target/healthy tissue ratio (lung/gastrointestinal) increased by ~60x with LFA1-P coated nanoparticles compared to controls.
- ICAM-1 targeting showed efficacy even in triple-negative breast cancers.
Conclusions:
- ICAM-1-targeted LFA1-P-coated GT DcNPs effectively deliver gemcitabine and paclitaxel combination therapy to metastatic breast cancer cells.
- This approach enhances drug localization in tumor tissues, particularly in lung metastases, and reduces off-target effects.
- ICAM-1-targeted nanoparticles represent a promising strategy for clinical development to improve therapeutic outcomes in advanced MBC, including triple-negative subtypes.
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