Synthesis of Water-Soluble Camptothecin–Polyoxetane Conjugates via Click Chemistry

Abstract

Water soluble camptothecin (CPT)-polyoxetane conjugates were synthesized using a clickable polymeric platform P(EAMO) that was made by polymerization of acetylene-functionalized 3-ethyl-3-hydroxymethyl oxetane (i.e., EAMO). CPT was first modified with a linker 6-azidohexanoic acid via an ester linkage to yield CPT-azide. CPT-azide was then click coupled to P(EAMO) in dichloromethane using bromotris(triphenylphosphine) copper(I)/N,N-diisopropylethylamine. For water solubility and cytocompatibility improvement, methoxypolyethylene glycol azide (mPEG-azide) was synthesized from mPEG 750 gmol−1 and click grafted using copper(II) sulfate and sodium ascorbate to P(EAMO)-g-CPT. 1H NMR spectroscopy confirmed synthesis of all intermediates and the final product P(EAMO)-g-CPT/PEG. CPT was found to retain its therapeutically active lactone form. The resulting P(EAMO)-g-CPT/PEG conjugates were water soluble and produced dose-dependent cytotoxicity to human glioma cells and increased γ-H2AX foci formation, indicating extensive cell cycle-dependent DNA damage. Altogether, we have synthesized CPT-polymer conjugates able to induce controlled toxicity to human cancer cells.

Synthesis and adhesive property study of polyoxetanes grafted with catechols via Cu(I)-catalyzed click chemistry

“…Anti-cancer drugs, fluorescent agents and other functional groups were clicked onto the backbone in an efficient manner. In cytotoxicity assessment study, the PEG-grafted polyoxetanes are compatible with human dermal fibroblasts at concentrations up to 2 mg/l [12,13]. Inspired by the work mentioned above, we envisioned that a catechol-containing polyoxetane might be an adjustable platform for alternative adhesive polymers to cPEG.…”

Synthesis of pH-sensitive, water-soluble paclitaxel prodrugs based on norbornene-functional polylactide by copper-free click chemistry

“…The conventional polymeric prodrugs based on biocompatible water-soluble polymers, such as poly(ethylene glycol) (PEG) and poly(N-(2-hydroxypropyl)-methacrylamide) (PHPMA), usually cannot readily be excreted from the body due to their nondegradability [8][9][10][11][12][13]. Aliphatic polyesters, such as polylactide (PLA) and poly(ε-caprolactone) (PCL), have been regarded as an excellent polymer carriers for drug delivery due to its nontoxicity, biocompatibility, and biodegradable [14][15][16].…”

Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug

“…16 Camptothecin has been used for the treatment of many different types of cancer despite its low water solubility and poor stability of the lactone form, a required form for therapeutic activity. 17 In particular, it is of advantage to use CPT to treat cancer as it selectively kills proliferating (S-phase) cells, thus exerting little to no toxicity to non-dividing normal cells resident of the brain. 18, 19 Polymer-CPT conjugates have been made by various methods.…”

“…18, 19 Polymer-CPT conjugates have been made by various methods. 20-22 Although several dendrimer-CPT derivatives have been made in the past, the efficiency using high capacity of dendrimer to deliver CPT was low. _ENREF_9 For instance, Thiagarajan et al applied EDC/NHS chemistry to conjugate CPT to the dendrimer via a glycine spacer.…”

“…It has proven to be a powerful strategy for precisely loading drugs to various polymeric carriers including dendrimers. 22, 24, 25 _ENREF_30 The current study reports on the use of click chemistry for the synthesis of water soluble polyamidoamine (PAMAM) dendrimer-camptothecin (CPT) prodrug conjugates towards development of an enabling modular dendrimer-based delivery system for cancer therapy. In particular, we applied CuAAC for improving coupling reaction efficiency and to synthesize CPT-dendrimer conjugates.…”