Development of a Hyaluronic Acid-Based Nanocarrier Incorporating Doxorubicin and Cisplatin as a pH-Sensitive and CD44-Targeted Anti-Breast Cancer Drug Delivery System

Abstract

Tumor-targeting nanomaterial-based chemotherapeutic drug delivery systems have been shown to represent an efficacious approach for the treatment of cancer because of their stability in blood circulation and predictable delivery patterns, enhanced tumor-selective drug accumulation, and decreased toxicity to normal tissues. The cell-surface transmembrane glycoprotein CD44 binds to the extracellular domain of hyaluronic acid (HA), and is overexpressed in breast, ovarian, lung, and stomach cancer. In this study, an HA-based nano-carrier incorporating doxorubicin (DOX) and cisplatin (CDDP) was synthesized as a CD44-targeting anti-cancer drug delivery system, and its tumor inhibition effects against CD44 + breast cancer cells were evaluated in vitro and in vivo . These dual drug-loaded HA micelles (HA-DOX-CDDP) exhibited significantly enhanced drug release under acidic conditions, and showed higher cellular uptake and stronger cellular growth inhibition than free drugs against 4T1 (CD44 + ) breast cancer cells. In contrast, no significant differences in growth inhibition and cellular uptake were observed between HA-DOX-CDDP and free drugs in NIH-3T3 (CD44 - ) control cells. Furthermore, HA-DOX-CDDP micelles exhibited stronger inhibitory effects and lower systemic toxicity than free drugs in a 4T1 mammary cancer-bearing mouse model, as determined using immunofluorescence and histological analyses. Therefore, HA-DOX-CDDP micelles represent a promising drug delivery system that exhibits acid-sensitive drug release, CD44-targeted delivery, and excellent biocompatibility and biodegradation. These properties resulted in excellent tumor accumulation and reduced adverse effects, indicating that HA-DOX-CDDP micelles have promising potential applications in chemotherapy for breast cancer.

Cannabidiol on the Path from the Lab to the Cancer Patient: Opportunities and Challenges

“…Anionic liposomes were shown to accumulate in BM and were then predominantly adsorbed by leukemic cells [ 154 ]. Hyaluronic acid, which shows a high binding affinity for the CD44 adhesion molecule, is present at enhanced concentrations in a variety of tumors and was also proposed for NC modification [ 159 , 160 ]. Experimental trials of novel delivery methods for CBD in cancer therapy are still scarce but have demonstrated promising results ( Table 3 ) [ 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ].…”

Self-Assembled Nanogels Based on Ionic Gelation of Natural Polysaccharides for Drug Delivery

“…HA, also named as hyaluronic acid and hyaluronate, is a linear and non-sulfated PS composed of repeating disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine units (Jeong et al, 2008). HA is highly negatively charged and a major component of the extracellular matrix of mammalian cells (Debele et al, 2016;Miao et al, 2018;Yu et al, 2020). Due to its excellent biocompatibility, low cost, non-immunogenicity, and water-binding properties, HA has been used for dermal filler, joint lubrication, prevention of surgical adhesion, dietary supplements, and eye drops (Valachova et al, 2016;Kim et al, 2017).…”

“…Interestingly, HA and cisplatin could also be co-assembled with a second drug to form multidrug NG (Figure 1C), thus easily realizing the combination therapy especially for cancer . The cationic-aromatic drugs (CA drugs) containing aromatic ring and positive charges, such as chemotherapeutics (Zhang et al, , 2018Yu et al, 2020;Ma et al, 2021), kinase inhibitors , and photosensitizers/dyes (Zhang and Tung, 2018a), could be easily self-assembled into the HA/Cis NG. The positive charges of CA drugs are believed to interact with HA through electrostatic interaction while the aromatic ring contributes to the hydrophobic interaction and π-π stacking of drugs, which collectively facilitates the encapsulation of CA drug into the NG.…”

Nanocarreadores aplicados ao tratamento do câncer de mama

“…As micelas de AH-DOX-CDDP, analisadas em um modelo de camundongo com câncer de mama, demonstraram menor toxicidade e melhores efeitos inibitórios do que drogas livres, de acordo com os testes utilizando imunofluorescência e análise histológica. Esse resultado demonstra que o composto AH-DOX-CDDP representa um sistema de medicamento animador, com excelente biocompatibilidade e biodegradação, relatando a promissora aplicação dessa medicação em quimioterapia para câncer de mama (Yu, 2020).…”