Targeting triple‐negative breast cancer with an aptamer‐functionalized nanoformulation: a synergistic treatment that combines photodynamic and bioreductive therapies

Abstract

Background Areas of hypoxia are often found in triple-negative breast cancer (TNBC), it is thus more difficult to treat than other types of breast cancer, and may require combination therapies. A new strategy that combined bioreductive therapy with photodynamic therapy (PDT) was developed herein to improve the efficacy of cancer treatment. Our design utilized the characteristics of protoporphyrin IX (PpIX) molecules that reacted and consumed O2 at the tumor site, which led to the production of cytotoxic reactive oxygen species (ROS). The low microenvironmental oxygen levels enabled activation of a bioreductive prodrug, tirapazamine (TPZ), to become a toxic radical. The TPZ radical not only eradicated hypoxic tumor cells, but it also promoted therapeutic efficacy of PDT. Results To achieve the co-delivery of PpIX and TPZ for advanced breast cancer therapy, thin-shell hollow mesoporous Ia3d silica nanoparticles, designated as MMT-2, was employed herein. This nanocarrier designed to target the human breast cancer cell MDA-MB-231 was functionalized with PpIX and DNA aptamer (LXL-1), and loaded with TPZ, resulting in the formation of TPZ@LXL-1-PpIX-MMT-2 nanoVector. A series of studies confirmed that our nanoVectors (TPZ@LXL-1-PpIX-MMT-2) facilitated in vitro and in vivo targeting, and significantly reduced tumor volume in a xenograft mouse model. Histological analysis also revealed that this nanoVector killed tumor cells in hypoxic regions efficiently. Conclusions Taken together, the synergism and efficacy of this new therapeutic design was confirmed. Therefore, we concluded that this new therapeutic strategy, which exploited a complementary combination of PpIX and TPZ, functioned well in both normoxia and hypoxia, and is a promising medical procedure for effective treatment of TNBC.

Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer

“…One primary mechanism of this hypoxia-mediated resistance to AR-targeted therapies is via upregulating AR signaling. Several studies have shown that overexpressing HIF-1α in PC cells stimulated AR signaling with the androgen dihydrotestosterone (DHT), enhanced AR transcriptional activity, and subsequently increased secretion of VEGF [ 21 , 22 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Specifically, hypoxia increased AR translocation to the nucleus and recruitment to the prostate-specific antigen (PSA) promoter [ 19 , 21 ].…”

“…The depletion of C1QBP in TNBC cells also decreased VCAM-1 expression and suppressed the activation of hypoxia-induced protein kinase C-nuclear factor-κappa B signaling [ 60 ]. The nano-treatment of TNBC in vitro and in vivo with the hypoxia-targeting drug tirapazamine, effectively abrogated tumor cell growth and progression in hypoxic regions [ 27 ]. The inhibition of TNBC hypoxia-induced NDBTs was shown to notably suppress migration and invasion in vitro and in vivo via attenuating the NDBT-mediated hypoxic phospho-signaling activation and modulating the expression of critical EMT-related genes, such as vimentin, which prevents downregulation of E-cadherin [ 57 ].…”

“…However, the role of hypoxia in potentially mediating therapeutic resistance to AR inhibitors in TNBC remains unknown. HIF-1α levels have been shown to be elevated in TNBCs relative to other BC subtypes demonstrating that TNBCs are able to grow under hypoxic conditions and thus resist treatments [ 27 ]. Herein, we explore and encourage investigation into the potential role of hypoxia in the resistance to therapies that target androgen or AR signaling in TNBC and provide evidence that the dual targeting of the hypoxia and AR signaling axes may help avert AR-targeted therapy resistance in AR-positive TNBC patients.…”

Iodinated cyanine dye-based nanosystem for synergistic phototherapy and hypoxia-activated bioreductive therapy

“…Fortunately, despite the greatly reduced therapeutic efficacy of PDT in hypoxic microenvironments, the induced hypoxia can be exploited for the activation of bioreductive precursors, to overcome the therapeutic resistance of the hypoxic tumors (Broekgaarden et al., 2017 ; Song et al., 2020 ; Chou et al., 2021 ). Unlike other strategies to relieve tumor anoxia, these bioreductive precursors can not only take advantage of the hypoxic microenvironment of the tumor itself but also make use of the unfavored hypoxic conditions to increase the effect of hypoxia-activated drugs (Liu et al., 2015 ; Zhang et al., 2018 ).…”

Conducive target range of breast cancer: Hypoxic tumor microenvironment

“…Considering such changes taken place in hypoxic tumor microenvironment, exploiting for selectively targeting hypoxic areas in breast cancer is an attractive strategy. Some mechanisms of hypoxia leading to drug resistance are being elucidated and drug delivery research has been moving to innovative strategies for breast cancer including engineered nanoparticle based drug/ gene delivery systems (9)(10)(11). In this review, we briefly discussed microenvironmental changes caused by hypoxia, which are mainly metabolic, genetic and immune levels, and systematically summarized promising advances in targeted hypoxia therapy for breast cancer.…”