Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line

Abstract

Glioblastoma multiforme (GBM) is the most common malignant primary neoplasm of the adult central nervous system originating from glial cells. The prognosis of those affected by GBM has remained poor despite advances in surgery, chemotherapy, and radiotherapy. Photochemical internalization (PCI) is a release mechanism of endocytosed therapeutics into the cytoplasm, which relies on the membrane disruptive effect of light-activated photosensitizers. In this study, phototherapy by PCI was performed on a human GBM cell-line using the topoisomerase II inhibitor etoposide (Etop) and the photosensitizer protoporphyrin IX (PpIX) loaded in nanospheres (Ns) made from generation-5 polyamidoamine dendrimers (PAMAM(G5)). The resultant formulation, Etop/PpIX-PAMAM(G5) Ns, measured 217.4 ± 2.9 nm in diameter and 40.5 ± 1.3 mV in charge. Confocal microscopy demonstrated PpIX fluorescence within the endo-lysosomal compartment, and an almost twofold increase in cellular uptake compared to free PpIX by flow cytometry. Phototherapy with 3 min and 5 min light illumination resulted in a greater extent of synergism than with co-administered Etop and PpIX; notably, antagonism was observed without light illumination. Mechanistically, significant increases in oxidative stress and apoptosis were observed with Etop/PpIX-PAMAM(G5) Ns upon 5 min of light illumination in comparison to treatment with either of the agents alone. In conclusion, simultaneous delivery and endo-lysosomal co-localization of Etop and PpIX by PAMAM(G5) Ns leads to a synergistic effect by phototherapy; in addition, the finding of antagonism without light illumination can be advantageous in lowering the dark toxicity and improving photo-selectivity.

Hyperbranched Polymers: Recent Advances in Photodynamic Therapy against Cancer

“…Among these co-treatments, the combination of PDT with chemotherapy is promising because of the high potential to eradicate cancer cells [ 136 , 137 , 138 , 139 ]. As reported, PDT treatment can affect the cell membrane permeability, and adding it as an adjuvant to chemotherapy may increase the deliverability of cytotoxic drugs [ 140 , 141 , 142 ]. Many studies have demonstrated that chemo-/photodynamic combination therapy can give excellent antitumor performances with the use of relatively low drug doses, even towards chemo-resistant cancers, and simultaneously overcome the limitations of PDT.…”

Drug Delivery in Photodynamic Therapy

“…The study employed etoposide (Etop) and protoporphyrin IX (PpIX) loaded into polyamidoamine dendrimers nanospheres. This formulation showed enhanced cellular uptake compared to free PpIX, and light irradiation resulted in increased synergistic effects, oxidative stress, and apoptosis compared to treatment with Etop and PpIX alone [ 4 ].…”