Dually Active Targeting Nanomedicines Based on a Direct Conjugate of Two Purely Natural Ligands for Potent Chemotherapy of Ovarian Tumors

Abstract

Actively targeted nanomedicines have promised to revolutionize cancer treatment; however, their clinical translation has been limited by either low targetability, use of unsafe materials, or tedious fabrication. Here, we developed CD44 and folate receptor (FR) dually targeted nanoparticulate doxorubicin (HA/FA-NP-DOX) based on a direct conjugate of two purely natural ligands, hyaluronic acid and folic acid (FA), for safe, highly specific, and potent treatment of ovarian tumors in vivo. HA/FA-NP-DOX had a small size and high DOX loading, wherein the particle size decreased from 115, 93, to 89 nm with increasing degree of substitution of FA from 6.4, 8.5, to 11.1, while increased from 80, 93, to 103 nm with increasing DOX loading from 15.0, 23.1, to 31.4 wt %. Interestingly, HA/FA-NP-DOX exhibited excellent lyophilization redispersibility and long-term storage stability with negligible drug leakage while it released 91% of DOX in 48 h at pH 5.0. Cellular studies corroborated that HA/FA-NP-DOX possessed high selectivity to both CD44 and FR, resulting in strong killing of CD44- and FR-positive SKOV-3 ovarian cancer cells while low toxicity against CD44- and FR-negative L929 fibroblast cells. In vivo studies revealed a long elimination half-life of 5.6 h, an elevated tumor accumulation of 12.0% ID/g, and an effective inhibition of the SKOV-3 ovarian tumor for HA/FA-NP-DOX, leading to significant survival benefits over free DOX·HCl and phosphate-buffered saline controls. These dually targeted nanomedicines are simple and safe, providing a potentially translatable treatment for CD44- and FR-positive malignancies.

Engineering precision nanoparticles for drug delivery

“…To further prevent non-specific distribution, many NP platforms have added targeting moieties to their surface to direct their delivery. Most targeting moietiesincluding antibodies 121 , glucose 122 , transferrin 34 , folate 123 , transporters 2 and integrin ligands 124 -use interactions with molecules on the target cell's surface, such as ligand-receptor, enzyme-substrate or antibodyantigen-mediated interactions 73 . Thus, targeted NPs must be engineered with a targeting moiety density that allows for these cell surface interactions, making it important to understand the ratio of receptors to ligands and the number of interactions needed to overcome the initial energy barrier to NP uptake 2,76 .…”

“…Antibodies, carbohydrates and other ligands on the NP surface can induce specific and efficient NP uptake 124 . Examples of tumour cell targeting moieties include antibodies 121 , peptides 126 , integrin ligands 124 , glucose 122 , transferrin 34,215 and folic acid 123 (fig. 5).…”

Recent progress of nanotechnology-based theranostic systems in cancer treatments

“…Another important organic drug carrier is HA, which is a primary CD44 binding molecule. Because CD44 is overexpressed and correlated with tumor progression in many types of cancers 29 , HA has been used in nanocarriers, with preferential tumor accumulation and increased cell uptake characteristics. Moreover, the biodegradation of HA is associated with hyaluronidase and oxidative stress 17 , which are associated with the progression of tumors, so that drug release from HA is more dependent on the tumor microenvironment.…”

Vitamin Drug conjugate: a systematic review of pharmacological potential

“…It is expected that marked medicines specifically taken up by target cells, can significantly improve the effectiveness of cancer therapy. In recent years, drugs containing different targeting ligands like polysaccharides, folate and peptides are tested to increase antitumor activity [6][7][8][9][10].…”