Fibroblast-Activation-Protein-Targeted Ferritin-Mediated Photodynamic Therapy

Ferritin is an iron storage protein found in numerous species including human beings. Each ferritin consists of 24 subunits which self-assemble into a 12-nm cage, with an 8-nm cavity. The pH-dependent dissociation and re-association of monomers provides a facile approach to encapsulate therapeutics into ferritin cages. Surface modification can also be readily achieved by either chemical conjugation or genetic engineering. These properties, along with the high biocompatibility, uniform size, and a long blood circulation half-life, make ferritin an appealing nanoplatform with wide applications in imaging and drug delivery. In particular, we loaded zinc hexadecafluorophthalocyanine (ZnF16Pc), a photosensitizer, into ferritin cage and investigated the conjugate for photodynamic therapy (PDT) against cancer. Further, we conjugated a single chain variable fragment (scFv) specific to fibroblast active protein (FAP) to ferritin surface. FAP is a protein upregulated in cancer associated fibroblasts (CAFs) but not normal fibroblasts. CAFs are the main stromal cell type in most solid tumors and play an important role in tumor growth and metastasis. We wonder what would occur if CAFs in tumors are selectively eliminated, and PDT, which produces short-traveled radicals for cytotoxicity, is an excellent tool for this investigation. Our studies showed that FAP-targeted PDT selectively killed CAFs not cancer cells in tumors, but the tumor growth was nonetheless significantly inhibited. Further investigation revealed that immune response was involved in the tumor suppression. We found in treated immunocompetent mice enhanced immunity not only against cancer cells but also CAFs.

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