Synthesis and Functions of Well-defined Polymer-drug Conjugates as Efficient Nanocarriers for Intravesical Chemotherapy of Bladder Cancer^a

Abstract

Novel poly(ethylene glycol) and poly(N-(2-hydroxypropyl)methacrylamide) block copolymer (PEG-b-PHPMA) with well-defined composition was synthesized by RAFT polymerization. Folate and doxorubicin (DOX) were quantitatively introduced into the copolymer. The influences of folate content and pH value on folate receptor (FR) mediated cell endocytosis and pH-responsive DOX release were studied. It has been demonstrated that minimum folate content is needed for the enrichment of hydrophobic folate on the hydrophilic part of polymer conjugates. The cytotoxicity of targetable polymer drug conjugates was much higher than that of non-targetable ones and free DOX. It could be concluded that the folate plays a significant role in targeting and internalization of the conjugates against bladder cancer cells.

Targeted polymer-drug conjugates: Current progress and future perspective

“…For example, PEG-block-PHPMA-DOX conjugates with 9.8 mol% FA content showed higher intracellular concentration than conjugate with 6.9 mol% FA, and the cell uptake level of conjugates with 3.1% FA content was the lowest and similar to that of non-targeted PEG-block-PHPMA-DOX conjugates. However, the highest FA content leads to conjugates take 24 h to dissolve in water [61]. Furthermore, the free carboxyl group, the H-bond forming groups, and the hydrophobic nature of the whole FA molecule which are exposed on the surface of conjugates, may also cause troubles during blood circulation, such as increased protein adsorption and accelerated blood clearance of conjugates [62].…”

Grafted copolymer micelles with pH triggered charge reversibility for efficient doxorubicin delivery

“…However, without uptake selection, polymeric micelles would be endocytosed by both normal cells and tumor cells during blood circulation, which leads to an unsatisfactory drug utilization and thus low therapeutic efficacy . To improve the specificity of drug delivery, targeting ligands such as folic acid and RGD peptide have been employed to functionalize the polymeric systems . These targeting ligands could actively bind to overexpressed specific receptors on tumor cell surfaces and facilitate the ligand‐receptor mediated endocytosis of polymeric micelles.…”

Folate receptor‐targeted aminoglycoside‐derived polymers for transgene expression in cancer cells

“…The FR is over‐expressed in ovarian, non‐small cell lung cancer, and triple‐negative breast cancers, and has therefore been employed to target therapeutic cargo to tumors. The receptor was also shown to be overexpressed in bladder cancer, although to a modest extent in some cases . Lower expression levels of the receptor on non‐malignant cells offer a window for selective destruction of cancer cells .…”

“…The receptor was also shown to be overexpressed in bladder cancer, although to a modest extent in some cases. [12][13][14][15][16] Lower expression levels of the receptor on non-malignant cells offer a window for selective destruction of cancer cells. 16 FR-mediated endocytosis has therefore been employed for delivering small molecules and nucleic acids to cancer cells that over-express the receptor.…”