Nanoparticles Composed of PEGylated Alternating Copolymer‐Combretastatin A4 Conjugate for Cancer Therapy

Abstract

Chemotherapy using vascular targeting agents is an emerging new approach for cancer therapy. Combretastatin A4 (CA4) is a leading vascular‐disrupting agent that targets the tumor blood vasculature for clinical tumor elimination. However, the extremely poor water solubility of CA4 hinders its biomedical applications. In this study, nanoparticles composed of novel PEGylated alternating copolymer‐CA4 conjugates are designed to improve the therapeutic efficiency of CA4. First, an alternating copolymer with an alkene‐pendant is synthesized by mPEG‐OH‐initiated ring‐opening copolymerization. Then, side carboxyl groups are introduced by a thio‐ene “click” chemical reaction, followed with CA4 conjugation through the Yamaguchi‐reaction, resulting in the target copolymer, mPEG‐b‐P(PA‐alt‐GCA4). Interestingly, the polymer‐drug conjugates can self‐assemble into nanoparticles with an average diameter of 55.6 nm. The in vitro drug release and cytotoxicity of the obtained CA4‐NPs toward 4T1 cells are investigated. Finally, the antitumor efficiency is evaluated in a 4T1‐tumor bearing murine model. The in vivo test results demonstrate that CA4‐NPs inhibited tumor growth much more efficiently at doses of 30 and 60 mg kg−1, compared with the control group.

A novel hypoxia‐activated polymeric Tirapazamine derivative for enhanced antitumor therapy

“…The residue was chromatographed on a silica gel column with ethyl acetate and n-hexane as an eluent to yield compound 3-(((4-nitrophenoxy) carbonyl) amino) benzo[e][1,2,4]triazine 1,4-dioxide (TPZ-NPC) as a yellow powder (600.0 mg). 1…”

“…The residue was chromatographed on a silica gel column with ethyl acetate and n-hexane as an eluent to yield compound 3-(3-(5-hydroxypentyl) ureido)benzo[e][1,2,4]triazine 1,4-dioxide (TPZH) as a red powder (270.5 mg). 1 H NMR (500 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.32-8.25 (m, 4H), 8.06-8.01 (m, 1H), 7.79-7.73 (m, 1H), 7.64-7.60 (t, 1H), 4.42-4.39 (t, 1H), 3.43-3.37 (q, 2H), 3.18-3.11 (q, 2H), 1.52-1.30 (m, 6H…”

“…Till now, cancer remains one of the major diseases causing the human death worldwide. [1][2][3][4] The main malignant tumors are solid tumors, and hypoxia is a common feature of solid tumors. 5,6 On the one side, the hypoxic microenvironments of tumors causes the failure of many anticancer therapies, including chemotherapy, phototherapy, and radiotherapy, leading to the proliferation and invasion of tumors by changing the expression of genes related to apoptosis and autophagy.…”

Advances in Engineered Biomaterials Targeting Angiogenesis and Cell Proliferation for Cancer Therapy

“…In vitro studies confirmed biocompatibility of CA4-NPs against 4T1 cells, and animal studies demonstrated enhanced therapeutic efficacy in 4T1-tumor bearing mice. [65] Sorafenib (SFN) is known to inhibit cancer cell proliferation and angiogenesis as it binds to VEGFR-2, VEGFR-3, and PDGFR-β, and is the only FDA approved medicine for treatment of advanced HCC. However, only 30 % patients respond to SFN, and clinical usage of SFN is limited due to its low response rate, poor water solubility, poor pharmacokinetic profile, and systemic side-effects.…”

Hydrophobic modified poly(l‐glutamic acid) graft copolymer micelles with ultrahigh drug loading capacity for anticancer drug delivery

“…Synthetic polypeptides are one of the most important and irreplaceable biomaterials, because of the advantages of high transport efficiency, low toxicity, no obvious restriction on the size of all substances, no inflammatory response 17–19 . Our group has developed a series of polypeptide‐based copolymers for anticancer drug delivery 20–24 . Specifically, poly( l ‐glutamic acid)‐ graft ‐poly(ethylene glycol) (PLG‐ g ‐PEG) was designed and synthesized for combretastatin A4 (CA4) conjugation.…”