pH‐Responsive PEG‐Shedding and Targeting Peptide‐Modified Nanoparticles for Dual‐Delivery of Irinotecan and microRNA to Enhance Tumor‐Specific Therapy

Abstract

Irinotecan is one of the main chemotherapeutic agents for colorectal cancer (CRC). MicroRNA‐200 (miR‐200) has been reported to inhibit metastasis in cancer cells. Herein, pH‐sensitive and peptide‐modified liposomes and solid lipid nanoparticles (SLN) are designed for encapsulation of irinotecan and miR‐200, respectively. These peptides include one cell‐penetrating peptide, one ligand targeted to tumor neovasculature undergoing angiogenesis, and one mitochondria‐targeting peptide. The peptide‐modified nanoparticles are further coated with a pH‐sensitive PEG‐lipid derivative with an imine bond. These specially‐designed nanoparticles exhibit pH‐responsive release, internalization, and intracellular distribution in acidic pH of colon cancer HCT116 cells. These nanoparticles display low toxicity to blood and noncancerous intestinal cells. Delivery of miR‐200 by SLN further increases the cytotoxicity of irinotecan‐loaded liposomes against CRC cells by triggering apoptosis and suppressing RAS/β‐catenin/ZEB/multiple drug resistance (MDR) pathways. Using CRC‐bearing mice, the in vivo results further indicate that irinotecan and miR‐200 in pH‐responsive targeting nanoparticles exhibit positive therapeutic outcomes by inhibiting colorectal tumor growth and reducing systemic toxicity. Overall, successful delivery of miR and chemotherapy by multifunctional nanoparticles may modulate β‐catenin/MDR/apoptosis/metastasis signaling pathways and induce programmed cancer cell death. Thus, these pH‐responsive targeting nanoparticles may provide a potential regimen for effective treatment of colorectal cancer.

Recent Advances in Understanding the Protein Corona of Nanoparticles and in the Formulation of “Stealthy” Nanomaterials

“…Conversely, the use of active targeting moieties and cell-penetrating peptides substantially enhances the NP uptake, but at the same time increases the formation of PC, facilitating their opsonization and, thus, reducing greatly their plasma half-life. This formulative dilemma has been undertaken by several groups, and many elegant solutions spawned by the combinations of stealthinducing and uptake-enhancing materials on the same NPs (Juang et al, 2019). These innovative formulations can switch their behavior depending on external stimuli: they can either respond to their chemical and biological milieu, or they can be "activated" by external stimuli.…”

Nanoparticles Modified with Cell-Penetrating Peptides: Conjugation Mechanisms, Physicochemical Properties, and Application in Cancer Diagnosis and Therapy

“…Therefore, many approaches for the covalent linkage of CPPs to NPs make use of the less frequent functionalities, such as thiols, that are present in cysteine. Free thiols can interact with maleimide residues to form a stable carbon-sulfur bond, as demonstrated by various groups for the covalent attachment of CPPs, such as RF, LMWP, or Tat to liposomes, dendrimers, or protein-based NPs [60][61][62]. Alternatively, the high affinity of noble metals to sulfur, which derives from the soft acid-soft base interaction, can be employed for the direct linkage of sulfhydryl-containing CPPs to the surface of metal NPs, as recently demonstrated for R8 and Tat conjugation to silver, gold, and palladium NPs [63][64][65][66][67].…”

MicroRNA‑608 promotes apoptosis via BRD4 downregulation in pancreatic ductal adenocarcinoma

“…Numerous studies have revealed the capacity of miRNAs to serve as promising therapeutic targets, and to be significant diagnostic or prognostic biomarkers in the treatment of malignant tumors (15)(16)(17). In addition, miRNA-608 has been widely reported to be a tumor suppressor gene and is downregulated Figure 3.…”