Targeted Chinese Medicine Delivery by A New Family of Biodegradable Pseudo-Protein Nanoparticles for Treating Triple-Negative Breast Cancer: In Vitro and In Vivo Study

Abstract

Triple negative breast cancer (TNBC) has the worst overall survival among all breast cancer subtypes; 80% of TNBC harbors TP53 mutation. Gambogic acid (GA) is an herbal compound isolated from the dry brownish gamboge resin of Garcinia hanburyi. A new family of biodegradable polymer, the folate (FA)-conjugated arginine-based poly(ester urea urethane)s nanoparticles (FA-Arg-PEUU NP), was developed as nano-carrier for GA. Its anti-TNBC effects and the underlying mechanism of action were examined. The average diameters of FA-Arg-PEUU NP and GA-loaded FA-Arg-PEUU NP (NP-GA) in water are around 165 and 220nm, respectively. Rhodamine-tagged FA-Arg-PEUU NP shows that the conjugation of FA onto Arg-PEUU NPs facilitates the internalization of FA-Arg-PEUU-NP into TNBC. Compared to free-GA at the same GA concentrations, NP-GA exhibits higher cytotoxicity in both TP53-mutated and non-TP53 expressed TNBC cells by increasing intrinsic and extrinsic apoptosis. In HCC1806-bearing xenograft mouse model, the targeted delivery of GA by the FA-Arg-PEUU-NP nano-carriers to the tumor sites results in a more potent anti-TNBC effect and lower toxicity towards normal tissues and organs when compared to free GA. Furthermore, NP-GA also reduces the tumor-associated macrophage (TAM) M1/M2 ratio, suggesting that the use of Arg-based nanoparticles as carriers for GA not only makes the surface of the nanoparticles positively charged, but also confers on to the nanoparticles an ability to modulate TAM polarization. Our data clearly demonstrate that NP-GA exhibits potent anti-TNBC effects with reduced off-target toxicity, which represents novel alternative targeted therapeutics for TNBC treatment.

Optimization of amino acid-based poly(ester urea urethane) nanoparticles for the systemic delivery of gambogic acid for treating triple negative breast cancer

“…The sections were subjected to hematoxylin and eosin (H&E) staining. For immunohistochemistry analysis of cleaved caspase-3, 20 tumor sections were incubated with anti-cleaved caspase-3 (1 : 400, cat#9664, Cell Signaling Technology), followed by incubation with HRP-conjugated secondary antibodies and 3,3′-diaminobenzidine and counterstained with hematoxylin. The slides were scanned using a digital pathology scanner (Leica BOND RX).…”

“…18,19 GA has been reported as a potential candidate for the treatment of triple negative breast cancer (TNBC) with poor response rates to traditional hormone therapy or HER2-targeted therapy. 19,20 In general, GA can regulate multiple molecular targets and promote the crosstalk between different anti-tumor mechanisms, which provides a promising alternative treatment modality to the conventional therapeutic approaches for TNBC.…”

Baicalein is a novel TLR4‐targeting therapeutics agent that inhibits TLR4/HIF‐1α/VEGF signaling pathway in colorectal cancer

“… 5 , 6 The binding of baicalein to TLR4 that inhibits the HIF‐1α/VEGF signaling pathway holds a promising therapy for metastatic CRC treatment. In the further, we would use target delivery system such as nanoparticles 7 or aptamers 8 to deliver baicalein to the tumor site that can further enhance its anti‐CRC effect.…”

Determination and tissue distribution comparisons of five xanthones after orally administering crude and processed gamboge

“…Gamboge is documented in traditional folk medicine records for the treatment of various diseases such as chronic dermatitis, hemorrhoids, bedsores and tapeworms (Zhang et al, 2012). During recent decades, a large number of pharmaceutical studies have focused on its antitumor activities and anti‐inflammatory activities (Kalita et al, 2021; Kwan et al, 2020; Panthong et al, 2007; Tan et al, 2017). As a natural product, gamboge is rich in caged polyprenylated xanthone components.…”

“…Gambogic acid (GA) is the most common and important member of the xanthone family, followed by other xanthones such as gambogenic acid (GNA), isogambogenic acid (IGNA) and β ‐morellic acid ( β ‐MA). In vitro and in vivo studies have reported that GA inhibits the growth of various tumors via different molecular mechanisms, including the induction of apoptosis, autophagy and cell cycle arrest, and the inhibition of invasion, metastasis and angiogenesis (Kashyap et al, 2016; Kwan et al, 2020; Suksen et al, 2021). In addition, GA also exerts anti‐inflammatory, antioxidant and antibacterial effects (Gunter et al, 2020; Liu et al, 2020).…”