Co-Encapsulation of Methylene Blue and PARP-Inhibitor into Poly(Lactic-Co-Glycolic Acid) Nanoparticles for Enhanced PDT of Cancer.

Jéssica A Magalhães,Denise C Arruda,Maurício S Baptista,Dayane B Tada

doi:10.3390/nano11061514

Jéssica A Magalhães, Denise C Arruda + Show 2 more

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https://doi.org/10.3390/nano11061514

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Abstract

The development of resistance against photodamage triggered by photodynamic therapy (PDT) is ascribed mainly to the cellular redox defenses and repair. If the tumor tissue is not promptly eliminated by the first few PDT sessions, PDT-resistance can be favored, challenging the efficacy of the treatment. Although the mechanism of PDT resistance is still unclear, in vitro assays have evidenced that it can be developed through the PARP damage-repair signaling pathway. Therefore, inhibition of poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) has the potential to increase PDT efficacy. This work reports on the synthesis of a controlled release system of a photosensitizer, methylene blue (MB) and a PARP-inhibitor, the veliparib. MB and veliparib were co-encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (VMB-NPs). A colloidal stable aqueous suspension of nanoparticles was obtained. The average hydrodynamic diameter was 90 nm and a narrow size distribution was obtained, with a polydispersity index (PDI) of 0.08. The release kinetics of MB and veliparib from VMB-NPs showed an initial burst of 8.7% and 58.3% release of the total amounts of MB and veliparib respectively, in the first 6 h, and a delayed release of up to 11.3% and 70%, in 19 days, for MB and veliparib, respectively. The VMB-NPs showed no cytotoxicity in the dark but the viability of B16F10-Nex2 cells decreased by 36% when the cells were irradiated (102 J/cm2, 660 nm) and treated with VMB-NPs containing 1.0 µM of MB and 8.3 µM of veliparib. Considering the increased photoactivity even at low MB and veliparib concentrations and the absence of cytotoxicity in dark, the co-encapsulation of MB and veliparib was shown to be a promising strategy to improve the PDT efficacy.

Highlights

Chemotherapy is the therapeutic protocol most recommended for cancer treatment.despite causing damages to tumor cells, the biodistribution of the anticancer drugs compromises their effective concentration in tumor tissues
Considering the previously reported in vivo lower efficiency despite of the encouraging results obtained in vitro of the combined use of PS and poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors, our research was focused on the co-encapsulation of a PS and a PARP inhibitor into a NP
In order to evaluate the effect of the methylene blue (MB) and veliparib loading on NPs parameters, the physical characteristics of the NPs, such as hydrodynamic diameter, polydispersity index (PDI) and zeta potential were measured in the presence and absence of the active molecules (Table 1)

Summary

Introduction

Chemotherapy is the therapeutic protocol most recommended for cancer treatment. Despite causing damages to tumor cells, the biodistribution of the anticancer drugs compromises their effective concentration in tumor tissues. A high dose of these drugs is required, and they affect tumor cells, and healthy cells, causing severe side effects. An alternative cancer treatment is photodynamic therapy (PDT), which is a minimally invasive procedure with less intense side effects and higher tumor selectivity. PDT involves the local activation of a photosensitizer (PS) by light irradiation in the presence of molecular oxygen. After PS activation, several photochemical pathways are triggered generating reactive oxygen species (ROS) which are responsible for inducing cell damage and cell death [1,2,3]

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