Abstract
Doxorubicin is employed alone or in combination for the treatment of several hematological and solid malignancies; despite its efficacy, there are associated cardiotoxicity limits both in its application in patients with heart disease risk factors and also in its long-term use. HFt-MP-PAS40 is a genetically engineered human ferritin heavy chain (HFt)-based construct able to efficiently entrap and deliver doxorubicin to cancer cells. HF-MP-PAS contains a short motif sequence (defined as MP) responsive to proteolytic cleavage by tumor matrix metalloproteases (MMPs), located between each HFt subunit and a masking polypeptide sequence rich in proline (P), alanine (A), and serine (S) residues (PAS). This carrier displayed excellent therapeutic efficacy in a xenogenic pancreatic cancer model in vivo, leading to a significant increase in overall animal survival in treated mice. Herein, we describe the HFt-MP-PAS40-Dox efficacy against squamous cell carcinomas of the head and neck (HNSCC) with the goal of validating the application of our nano-drug for the treatment of different solid tumors. In addition, a tolerability study in healthy mice was also performed. The results indicate that HFt-MP-PAS40-Dox produced increased anti-tumor effects both in vitro and in vivo in comparison to the free drug in several HNSCC cell lines. In the acute toxicity studies, the maximum tolerated dose (MTD) of HFt-MP-PAS40-Dox was about 3.5 higher than the free drug: 25 mg/kg versus 7 mg/kg doxorubicin equivalents. Importantly, evaluation of heart tissues provided evidence that doxorubicin is less cardio-toxic when encapsulated inside the ferritin carrier. In conclusion, HFt-MP-PAS40-Dox may be administered safely at higher doses compared with the free drug, resulting in superior efficacy to control HNSCC malignancies.
Highlights
Human ferritin heavy chain (HFt)-based carriers have been shown to efficiently deliver chemotherapeutics to cancer cells [1,2,3,4,5,6,7,8]
It was reported that a wide number of tumors express up to 100 times higher levels of transferrin receptor 1 (TfR1) than healthy cells and actively internalize the HFt:TfR1 ligand-receptor complex to accumulate large amounts of iron required for the growth of cancer cells [16,17]
This higher yield was mainly ascribed to the stabilizing effect of the PAS polymer toward the extreme conditions required by the pH-jump used to dissociate and re-associate the 24-mer assembly
Summary
Human ferritin heavy chain (HFt)-based carriers have been shown to efficiently deliver chemotherapeutics to cancer cells [1,2,3,4,5,6,7,8]. We have developed a novel HFt-based construct, named HFt-MP-PAS40, suitable for drug delivery This was dictated by the necessity of increasing both the in vivo half-life of native HFt and the stability of HFt-drug complexes produced. This construct is characterized by an N-terminus of each HFt subunit genetically fused to: (i) a PAS polypeptide sequence of 40 residues rich in proline (P), alanine (A), and serine (S) residues [4,18]; and (ii) a short motif sequence (defined as MP) responsive to proteolytic cleavage by tumor matrix metalloproteases (MMPs), inserted between each HFt subunit and the outer PAS polypeptide. The presence of the MP sequence allows the PAS shield to be selectively removed by a specific stimulus present in the tumor microenvironment so that the resulting unmasked HFt can freely be internalized by TfR1 overexpressed in tumor cells
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