Effective Delivery of Paclitaxel-Loaded Ferritin via Inverso CendR Peptide for Enhanced Cancer Therapy

Abstract

The application of drug delivery systems based on ferritin nanocarrier has been developed as a potential strategy in cancer therapy. The limited permeability of ferritin remains a challenge for drug penetration into the deeper tumor tissues. CendR peptides have been reported to bear tumor-specific penetration by recognizing neuropilin (NRP-1) receptor that overexpressed on a wide range of cancer cells. Herein, we modified CendR peptide L(RGERPPR), its retro-inverso peptide D(RPPREGR), and inverso peptide D(RGERPPR) on the outer surface of human H chain ferritin by sulfhydryl-maleimide coupling reaction. Approximately 45 paclitaxel (PTX) molecules could be loaded into each ferritin inner cavity by a thermal-triggered method at a specific ionic strength. The penetration ability of three peptide-modified ferritin constructs showed that D(RGERPPR)-modified HFtn was able to be engulfed by A549 and MCF-7 tumor cells and spheroids at the highest level. Due to the dual-targeting effect of ferritin and modified peptides, the PTX-loaded nanocomposites could effectively enter the cells with high expression of TfR1 and NRP-1 receptors and enhanced the cytotoxicity against tumor cells. Remarkably, H-D(RGE)-PTX displayed a superior tumor growth suppression efficacy in A549 tumor-bearing nude mice. The inverso CendR peptide-modified HFtn nanocarrier was first generated and could provide an effective dual-targeting platform for treatment of cancers.

Advancements of the Molecular Directed Design and Structure–Activity Relationship of Ferritin Nanocage

“…For instance, tumor-specific peptide-modified ferritin-paclitaxel nanoparticles produce efficient toxicity to tumor cells due to the dual targeting of ferritin and modified peptides, providing an effective dual-targeting platform for tumor treatment. 195 Represented by doxorubicin (Dox)-loaded ferritin nanoparticles, 79,196 Simsek and Kilic first reported the encapsulation of anticancer drugs in ferritin by encapsulating Dox into ferritin in 2005. 197 Subsequent studies have focused on genetically/ chemically modified HuHF-anticancer drug nanomedicines to investigate their targeting and therapeutic properties.…”

“…Moreover, based on the endogenous receptor-mediated BBB transcytosis and tumor targeting of HuHF, a series of targeted delivery systems were constructed. For instance, tumor-specific peptide-modified ferritin-paclitaxel nanoparticles produce efficient toxicity to tumor cells due to the dual targeting of ferritin and modified peptides, providing an effective dual-targeting platform for tumor treatment . Represented by doxorubicin (Dox)-loaded ferritin nanoparticles, , Simsek and Kilic first reported the encapsulation of anticancer drugs in ferritin by encapsulating Dox into ferritin in 2005 .…”

Design and fabrication of intracellular therapeutic cargo delivery systems based on nanomaterials: current status and future perspectives

“…For example, Sun et al constructed a novel redox-sensitive drug delivery system in which micelles rapidly release the drug inside the cell when glutathione reduces the disulfide bond. 309 Moreover, human h-chain ferritin (HFn) has been shown to bind transferrin receptor 1 (TfR1) overexpressed in many tumors, 310,311 giving it a strong active targeting ability against tumors. Based on this, Cai et al selected HFn as a gatekeeper to seal MSNs modified by 2-2 0 disulfide pyridines through disulfide bonds to prevent the early release of Dox, while the HFn nanovalves thus featured to release drugs triggered by intracellular redox reactions.…”

Developing a Hetero-Trinuclear Erbium(III)–Copper(II) Complex Based on Apoferritin: Targeted Photoacoustic Imaging and Multimodality Therapy of Tumor

“…At the same time, we should overcome the shortcomings of metal complexes, such as lack of targeting ability and significant off-target toxicity, which brought out serious systemic toxicity in vivo . At present, protein-based drug delivery systems have been one of the most promising strategies to overcome these shortcomings. − Indeed, apoferritin (AFt) is an ideal candidate due to its nanoscale structure, biocompatibility, biodegradability, and nontoxicity. − …”