Multifunctional dendrimer/combretastatin A4 inclusion complexes enable in vitro targeted cancer therapy

Abstract

Background:We report here a unique approach to using multifunctional dendrimer/ combretastatin A4 (CA4) inclusion complexes for targeted cancer therapeutics. Methods: Amine-terminated generation 5 polyamidoamine dendrimers were first partially acetylated to neutralize a significant portion of the terminal amines, and then the remaining dendrimer terminal amines were sequentially modified with fluorescein isothiocyanate as an imaging agent and folic acid as a targeting ligand. The multifunctional dendrimers formed (G5.NHAc-FI-FA) were utilized to encapsulate the anticancer drug, CA4, for targeted delivery into cancer cells overexpressing folic acid receptors. Results: The inclusion complexes of G5.NHAc-FI-FA/CA4 formed were stable and are able to significantly improve the water solubility of CA4 from 11.8 to 240 µg/mL. In vitro release studies showed that the multifunctional dendrimers complexed with CA4 could be released in a sustained manner. Both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and morphological cell observation showed that the inhibitory effect of the G5.NHAc-FI-FA/CA4 complexes was similar to that of free CA4 at the same selected drug concentration. More importantly, the complexes were able to target selectively and display specific therapeutic efficacy to cancer cells overexpressing high-affinity folic acid receptors. Conclusion: Multifunctional dendrimers may serve as a valuable carrier to form stable inclusion complexes with various hydrophobic anticancer drugs with improved water solubility, for targeting chemotherapy to different types of cancer.

MRI Monitoring of Cerebral Blood Flow after the Delivery of Nanocombretastatin across the Blood Brain Tumor Barrier

“…The size of G3-CA4 conjugate was estimated to be approximately 3 to 5 nm using transmission electron microscope (TEM) images as shown in Figure 1C. The G3-CA4 polymer conjugate (Figure 1A) was highly water soluble, while natural free CA4 was water insoluble [38]. Therefore, we succeeded in conjugating a water insoluble CA4 with highly soluble G3 polymers that bear an additional advantage as a prodrug with enhanced aqueous solubility which in turn increase the bioavailability of the drug that will result in enhanced cytotoxic activity.…”

Targeted‐nanoliposomal combretastatin A4 (CA‐4) as an efficient antivascular candidate in the metastatic cancer treatment

“…In this way, nanoparticle‐based delivery systems are the other strategies that have been used to not only improve bioavailability CA‐4 but also decrease its side effects. It has been attempted to load CA‐4 in different nanocarriers, such as liposomes nanoparticles (Huang et al, ; Moiseeva et al, ; Nallamothu, Wood, Kiani, et al, ; Nallamothu, Wood, Pattillo, et al, ; Yang et al, ; Y. Zhang, Wang, Bian, Zhang, & Zhang, ), polymeric micelles polyethylene glycol–polylactic acid (PEG‐PLA; Wakaskar et al, ; Y. Wang et al, ; Y. Wang et al, ; Yang et al, ), pH‐sensitive pullulan‐based nanoparticles (Y. Wang et al, ), thermosensitive PLA core/poly( N ‐isopropylacrylamide) shell fibers, dendrimers (M. Zhang et al, ), and nanocapsules (Z. Wang & Ho, ), to decrease side effects, increase blood circulation of the drug and then enhance bioavailability of CA‐4.…”

“…Zhang, Wang, Bian, Zhang, & Zhang, 2010), polymeric micelles polyethylene glycol-polylactic acid (PEG-PLA; Wakaskar et al, 2015;Yang et al, 2012), pH-sensitive pullulan-based nanoparticles (Y. Wang et al, 2013), thermosensitive PLA core/poly(N-isopropylacrylamide) shell fibers, dendrimers (M. Zhang et al, 2011), and nanocapsules (Z. Wang & Ho, 2010), to decrease side effects, increase blood circulation of the drug and then enhance bioavailability of CA-4.…”

Combretastatin A4 Regulates Proliferation, Migration, Invasion, and Apoptosis of Thyroid Cancer Cells via PI3K/Akt Signaling Pathway

“…Combretastatin A4 (CA4), a natural product isolated from the South African tree Combretum caffrum , is a potential therapeutic candidate for cancer treatment [7,8]. CA4 as an antimitotic agent can strongly cause vascular shutdown and cell death in tumors by binding the colchicine binding site of tubulin to block microtubule assembly [9].…”