Drug-Carrying Capacity and Anticancer Effect of the Folic Acid- and Berberine-Loaded Silver Nanomaterial To Regulate the AKT-ERK Pathway in Breast Cancer

Abstract

Currently, in clinics, breast cancer is treated with free chemotherapeutic drugs, as a result there is not much therapeutic effect in treated models, leading to substantial systemic toxicity. To overcome these critical problems for the primary outcome, we developed the formulated nanomaterial (FA-PEG@BBR-AgNPs) aimed to specifically target cancer cells via nanoscopic-based drug delivery for getting better therapeutic effectiveness. In the present study, an isoquinoline alkaloid, berberine (BBR), was chosen as a cancer therapeutic agent, encapsulated on citrate-capped silver nanoparticles (AgNPs) through electrostatic interactions (BBR-AgNPs). Then, BBR-AgNPs were conjugated with polyethylene glycol-functionalized folic acid (FA-PEG) via hydrogen bonding interactions (FA-PEG@BBR-AgNPs). The transmission electron microscopy study shows the cellular invasion of the formulated FA-PEG@BBR-AgNPs, indicating the accretion of the nanomaterial at the tumor-specific site. Hence, FA conjugated with the nanomaterial suggests an efficient release of BBR molecules into the specific cancer site. Consequently, the results showed an increase in apoptotic induction via reactive oxygen species and condensed nuclei in cancer cells. Moreover, the western blotting analysis shows reduced/increased expression of PI3K, AKT, Ras, Raf, ERK, VEGF, HIF1α, Bcl-2, Bax, cytochrome c, caspase-9, and caspase-3, thereby enhancing apoptosis. Likewise, the in vivo antitumor efficiency of FA-PEG@BBR-AgNPs showed a significant restraint of tumor progression, and histopathological observations of lung, liver, kidney, heart, and brain tissues proved lesser toxicity of FA-PEG@BBR-AgNPs. Thus, the successfully formulated nanomaterial can serve as a potential drug-discharging vehicle to combat cancer cells by a molecular-based targeting approach.

Utilização de Nanopartículas no Tratamento do Câncer: Aspectos Gerais, Mecanismos de Ação Antineoplásicos e Aplicabilidades Tumorais

“…Os íons de prata são capazes de induzir citotoxicidade celular por intermédio do aumento da instabilidade de sódio e potássio nos canais iônicos da membrana celular, que desestabiliza a mitocôndria e libera ERO, levando a célula à morte 19 . Apesar da sua eficiência em geração de ERO e morte tumoral, no estudo feito por Bhanumathi et al 26 , foram observados leves efeitos citotóxicos em tecidos saudáveis de camundongos que teriam sido expostos à NP de prata no coração, rim, cérebro e pulmão.…”

“…Em contraste com os redutores naturais utilizados nos estudos de Bahahara et al 28 e He et al 29 , o experimento apresentado por Bhanumathi et al 26 utiliza o composto químico boro-hidreto de sódio (NaBH 4 ) como agente redutor de NP de prata. No estudo de Bhanumathi et al 26 , as NP de prata carrearam ácido fólico e berberina em seu interior, causando uma diminuição de mais de 80% na viabilidade celular de células cancerígenas mamarias.…”

“…Em contraste com os redutores naturais utilizados nos estudos de Bahahara et al 28 e He et al 29 , o experimento apresentado por Bhanumathi et al 26 utiliza o composto químico boro-hidreto de sódio (NaBH 4 ) como agente redutor de NP de prata. No estudo de Bhanumathi et al 26 , as NP de prata carrearam ácido fólico e berberina em seu interior, causando uma diminuição de mais de 80% na viabilidade celular de células cancerígenas mamarias. Outro importante dado é demonstrado no estudo de Bhanumathi et al 26 , que expuseram NP de prata conjugadas com ácido fólico e beberina a células saudáveis da mama, sendo observado que o efeito tóxico de viabilidade celular em relação a essas células foi cerca de 20% em 48 horas, concluindo que células normais de mama não seriam gravemente afetadas quando expostas ao conjugado de NP de prata.…”

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

“…It is worth reiterating that poor intestinal absorption, extensive efflux by the action of P-gc and extensive degradation account to the rather poor bioavailability/pharmacokinetics profile of berberine. The various formulation approaches specifically designed to tackle this problem and improve berberine's anticancer efficacy are shown in Table 2 [106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123]. These include nanoparticles of various sizes and surface charges with some specifically targeting subcellular organelles, such as the mitochondria.…”

“…Bhanumathi et al [116] Hypoxia-specific chemo-targeting iron-oxide nanoparticle-Berberine complexes Hypoxic cell-sensitizer sanazole (SAN) -directed targeting of cytotoxic drug berberine and iron-oxide nanoparticle complexes.…”