Enhancement of Tumor Homing by Chemotherapy‐Loaded Nanoparticles

Abstract

Targeted delivery of anticancer drugs with nanocarriers can reduce side effects and ameliorate therapeutic efficacy. However, poorly perfused and dysfunctional tumor vessels limit the transport of the payload into solid tumors. The use of tumor‐penetrating nanocarriers might enhance tumor uptake and antitumor effects. A peptide containing a tissue‐penetrating (TP) consensus motif, capable of recognizing neuropilin‐1, is here fused to a neuroblastoma‐targeting peptide (pep) previously developed. Neuroblastoma cell lines and cells derived from both xenografts and high‐risk neuroblastoma patients show overexpression of neuropilin‐1. In vitro studies reveal that TP–pep binds cell lines and cells derived from neuroblastoma patients more efficiently than pep. TP–pep, after coupling to doxorubicin‐containing stealth liposomes (TP–pep–SL[doxorubicin]), enhances their uptake by cells and cytotoxic effects in vitro, while increasing tumor‐binding capability and homing in vivo. TP–pep–SL[doxorubicin] treatment enhances the Evans Blue dye accumulation in tumors but not in nontumor tissues, pointing to selective increase of vascular permeability in tumor tissues. Compared to pep–SL[doxorubicin], TP–pep–SL[doxorubicin] shows an increased antineuroblastoma activity in three neuroblastoma animal models mimicking the growth of neuroblastoma in humans. The enhancement of drug penetration in tumors by TP–pep‐targeted nanoparticles may represent an innovative strategy for neuroblastoma.

Combined Replenishment of miR‐34a and let‐7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models

“…To this end, we used the same orthotopic model of NB planned for therapeutic studies, obtained by implantation of IMR‐32 cell line into the adrenal gland of athymic mice. [ 46,47 ] No weight loss, splenomegaly or skin rash were evidenced in all treatment groups, as well as no acute or chronic liver and kidney toxicities emerged by the quantification of AST, ALT, CRE, BUN levels in mice plasma ( Figure A,B).To rule out that the TL[miR] treatments may have an immune‐stimulatory activity, we quantified levels of 14 proinflammatory cytokines performed 6 h after the first treatment (acute immune activation, Figure 3C) and 24 h after the last treatment (late immune response, Figure 3D). This analysis confirmed that our TL[miR] did not increase cytokine levels, even when administered at the maximum dose (combo = 20 µg + 20 µg miR‐mimics per mouse).…”

Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy

“…Human (IMR-32, HTLA-230, SH-SY5Y and SK-N-AS) and murine (NXS2) neuroblastoma (NB) cell lines were grown in complete Dulbecco’s Modified Eagle Medium (DMEM) medium, as previously described [ 12 – 15 ]. In some experiments, IMR-32 cells were infected with retrovirus expressing the firefly luciferase (luc) gene, as previously reported [ 13 ].…”

Overcoming Biological Barriers in Neuroblastoma Therapy: The Vascular Targeting Approach with Liposomal Drug Nanocarriers

“…A recent study has shown that the resulting peptide (CRALKYSHSHSYWLRSGGG) is indeed an excellent bifunctional ligand for targeting of NB cells. This peptide when coupled to doxorubicin‐loaded liposomes increased tumor uptake, penetration, and diffusion of the payload in tumor tissues (see Figure ) and improved the antitumor effects in three xenografts of human NB …”

“…In particular, the therapeutic properties of DXR nanoformulations tagged with ligands capable of recognizing aminopeptidase N (APN) or A (APA) or other receptors expressed by the tumor endothelium and pericytes, or capable of targeting GD 2 expressed by NB cells, either alone or in combination, will be reviewed and discussed. Finally, we will review recent data regarding the identification and development of new tumor‐homing and tumor‐penetrating peptides (discovered by screening peptide‐phage libraries on NB mouse xenografts and patient specimens and, in some cases, fused with a motif capable of recognizing neuropilin‐1 (NRP‐1)), as well as their capability to increase liposomal drug delivery and penetration into NB tissues …”