Targeted Nanodrugs to Destroy the Tumor Extracellular Matrix Barrier for Improving Drug Delivery and Cancer Therapeutic Efficacy

Abstract

One of the main reasons why most cancer patients do not respond well to chemotherapy is that drugs cannot accumulate in tumors at an optimal dose, eventually resulting in failure to prevent cancer cell growth. To improve drug delivery efficiency, we engineered a highly efficient tumor-targeted and stroma-breaking nanocarrier by the modification of iron oxide nanoparticles (IONPs) with a tumor-targeting peptide c(RGDyK) and a hyaluronidase (HAase) on the surface. The yielding nanocomplex, c(RGDyK)-HAase-IONP, targeted the tumor by binding integrin αvβ3 and went deeply into the tumors by the degradation of hyaluronic acid (HA), which was highly expressed in the tumor extracellular matrix (ECM). Good biostability and a low pH preferred drug release profile were characterized for c(RGDyK)-HAase-IONP carrying DOX in vitro. c(RGDyK)-HAase-IONP showed an improved tumor-targeting (2.5 times higher) effect after intravenous injection in the MC38 tumor-bearing mice model, as determined by whole-body fluorescence imaging compared to the non-targeted IONPs without HAase. After 5 systemic treatments, c(RGDyK)-HAase-IONP/DOX (5 mg/kg of equivalent dose of DOX) significantly inhibited MC38 tumor growth (22.1 ± 7.4 times relative to the non-treated group). Elevated apoptosis and reduced proliferation in the tumor cell were detected in the c(RGDyK)-HAase-IONP/DOX treated tumors compared to the control groups. Overall, the highly efficient targeted nanocarrier c(RGDyK)-HAase-IONP demonstrated tremendous potency for improving drug delivery and tumor therapy efficacy by targeted degradation of the dense HA barrier in the tumor ECM. We determined that such a tumor stroma–degrading nanosystem was capable of reducing tumor recurrence and drug resistance and could ultimately improve clinical tumor treatment responses.

Hyaluronic Acid Modified Metal Nanoparticles and Their Derived Substituents for Cancer Therapy: A Review

“…In vitro, c(RGDyK)-HAase-IONP carrying DOX showed good biostability and a preferred drug release profile at low pH. After intravenous injection in MC38 tumor-bearing mice model, c(RGDyK)-HAase-IONP exhibited a 2.5 times higher tumor-targeting effect [ 107 ].…”

Polyvinylpyrrolidone Assisted One-Pot Synthesis of Size-Tunable Cocktail Nanodrug for Multifunctional Combat of Cancer

“… 5 , 6 Recent studies have revealed that in vivo barriers and multidrug resistance (MDR) of cancer cells might contribute significantly to this drawback. 7 , 8 In vivo barriers encompass the complex physiological environment within living organisms that can impede the effective delivery and distribution of therapeutic agents to target cancer cells. 9 Factors such as the tumor microenvironment, 10 heterogeneous blood supply and drug metabolism, 11 and the presence of physiological barriers like the blood–brain barrier 12 contribute to the intricate landscape that influences drug accessibility and efficacy.…”