Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs.

IR820‐loaded PLGA nanoparticles for photothermal therapy of triple‐negative breast cancer

“…23,24 For example, apoptosis can be achieved as the primary mechanism of cell death by using lower energy irradiation. 23,24 For example, apoptosis can be achieved as the primary mechanism of cell death by using lower energy irradiation.…”

“…Since the mechanism of cell death is influenced by the level of tumor heating achieved during treatment, it is important to note that there are several parameters that influence heat production in NP-mediated PTT, including the photothermal conversion efficiency of the NPs, the energy of irradiation applied, the density of the surrounding tissue, and even the localization of the NPs within the target cells and tissue. 23,24 For example, apoptosis can be achieved as the primary mechanism of cell death by using lower energy irradiation. 8,[25][26][27] To control NP localization in the tumor microenvironment, targeting agents could be incorporated into the NP design, but there is currently substantial debate surrounding the benefit provided by this strategy, as targeted NPs may not offer a dramatic benefit compared to NPs that rely on strictly passive tumor accumulation.…”

Photothermal Therapy Generates a Thermal Window of Immunogenic Cell Death in Neuroblastoma

“…To answer these questions, we utilize Prussian blue nanoparticles (PBNPs) for PTT (PBNP‐PTT) ( Figure A; Figure S1, Supporting Information). PBNPs are biodegradable, the United States Food and Drug Administration (FDA)‐approved nanoparticles that we have previously used for PTT of tumors, both alone and in combination with chemotherapy and immunotherapies . Specifically, we administer varying thermal doses of PBNP‐PTT to tumor cells in vitro and in vivo by varying the PBNP concentrations and the laser power.…”

Mutually Synergistic Nanoparticles for Effective Thermo‐Molecularly Targeted Therapy

“…[8,21a,23] Thus, we evaluated the effect of CA‐Micelles and C‐Micelles on the p‐ERK1/2 levels in A549 cells. Obviously, C‐Micelles with irradiation caused a much lower expression of p‐ERK1/2 level as compared to C‐Micelles without irradiation, indicating that the photothermal effect might account for the effective inhibition on p‐ERK1/2 (Figure C and Figure S12, Supporting Information) . In particular, CA‐Micelles further exhibited a much lower level of p‐ERK1/2 under irradiation as compared to C‐Micelles under irradiation (Figure C and Figure S12, Supporting Information), suggesting that 17AAG within the micelles can effectively inhibit the p‐ERK1/2 level as well, in addition to photothermal effect.…”

“…[21a] Apparently, CA‐Micelles can synergistically reduce the p‐ERK level through both targeting of 17AAG to HSP90 and photothermal destruction. [8,21a,23b,24,25]…”