Design, synthesis and antitumor activity of a novel PEG-A6-conjugated irinotecan derivative

 

 

 

Yang-Qing Huanga,b,c,e, Jian-Dong Yuanb,e, Hai-Feng Dingb, Yun-Song Songb, Gang Qianb, Jia-Li Wangb, Min Jia, Ye Zhang

We have designed and synthesized a novel PEG-A6-conjugated irinotecan derivative 8 as antitumor agent.  It is known that the success of chemotherapy for the treatment of tumors mainly relies on the drug and its dosage, particularly how efficiently it is delivered to the tumor cells. Due to their nonspecific action, many anticancer drugs usually exert toxicity to normal tissue even at their optimal condition. To a great extent, this issue could be ad- justed by precise targeting of anticancer drug to cancer cells. In the past decade, various tumor-targeted delivery systems have been designed and developed as promising drug carriers taking advantage of the un- ique enhanced permeation and retention (EPR) effect described by solid tumors.1–6 There is a growing number of evidence to prove that tar- geted delivery of anticancer drug can efficiently improve drug accu- mulation in tumors and therapeutic effects (by EPR) while minimizing toxicity.

 

As one of famous drug carrier systems, poly (ethylene glycol) (PEG), which exhibits well documented properties including water solubility, biocompatibility, and low immunogenicity, has been granted food and drug administration (FDA) approval for human usage.7,8 In addition, it has been proved that PEGylation can reduce cytotoxicity and increase the circulation time in the bloodstream and consequently enhancing the in vivo tumor accumulation of the therapeutic agent via the EPR effect, which finally improve the antitumor activity.7,8 The development of NKTR-102 is a good illustration. Therefore, PEGylation has been widely designed and used as antitumor drug carrier. However, the extent of passive tumor-targeting alone via the EPR effect of PEGylation is usually very limited.9,10 It has been proved that PEGylated drug carriers modified with active tumor targeting ligands specific to receptors overexpressed in cancer cells may further improve the in vivo tumor accumulation of drug carriers.11–17 It is well established that anticancer peptide is a resourceful strategy for the molecularly targeted cancer drug discovery and development process.18 Some peptides containing the arginine-glycine-aspartic acid (RGD) and polypeptide A6 have been widely introduced in targeted delivery to develop new antitumor agents with high efficiency and low toxicity.19–23 As a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin re- ceptors (consists of α and β subunits, mainly including αvβ3, αvβ5 and αvβ6, etc.), the RGD peptide plays an important role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis, 19-21 while the 8 amino-acid peptide A6 has been shown to strongly bind to CD44 and thus to exhibit antitumor and antimetastatic properties.22–24 RGD and A6 have been proven to be active and effective tumor-tar- geting ligangs and widely used for the delivery of anticancer drugs to tumors.22–25 Our interesting on the function of PEG and peptide inspires us to expect that the combination of PEGylation and peptide mod- ification with antitumor agents may lead to better antitumor efficiency, lower toxicity and water solubility. So this tumor-targeted delivery system (PEGylation and peptide modification) has been selected in the present work.

 

As a well-known topoisomerase 1 (Top1) inhibitor, irinotecan is a widely used chemotherapeutic agent.26 However, its therapeutic use is heavily hindered by its low solubility in aqueous media, high toxicity and rapid inactivation by lactone ring hydrolysis in vivo. To solve these problems, PEGylation and peptide modification was thus synchronously designed and conducted on the skeleton of irinotecan to offer a PEG- cRGD-conjugated irinotecan derivative (BGC0222) in our previous work.27 Our previous work27 showed that BGC0222 may exert the antitumor effect by binding to αvβ3 target and consequently inducing neovascularization effect, due to the presence of cRGD. In addition, BGC0222 could slowly and steadily release irinotecan, which was subsequently metabolized into 7-ethyl-10-hydroxycamptothecin (SN- 38).27 The success of BGC0222 indicated that the PEGylation and peptide modification of irinotecan could lead to better efficiency and lower toxicity. However, it is believed that there is still some room for improvement of the targeting and consequent to better efficiency, due to its limited binding/interacting points and space in the chemical structure. In the present work, as a continuation of the previous work, a novel PEG-A6-conjugated irinotecan derivative 8, which contain a different chained A6 group and may lead to more binding/interacting points and space in comparison with BGC0222, was designed and synthesized as potential antitumor agent. It is considerable to expect that the replacement of A6 with cRGD may increase the targeting binding/interacting points and space and thus lead to better antitumor activity.

 

The target compound 8 was synthesized through six steps as outlined in Scheme 1. Firstly, the esterification of irinotecan 1 with BOC- Glycine offered 2 in good yield, in the presence of 4-dimethylamino- pyridine (DMAP) and N, N'-dicyclohexylcarbodiimide (DCC), according to our previous work.27 Secondly, the treatment of 2 with tri- fluoroacetic acid (TFA) offered 3 in almost quantitative yield through the hydrolytic reaction of Boc-amide.27 Thirdly, the combination of 3 and commercial compound 4 provided 5 in moderate yield, in the presence of N,N-Diisopropylethylamine (DIEA) and diethyl pyr- ocarbonat (DEPC). In the step 4, the treatment of 5 with TFA offered 6 in good yields, in the presence of dichloromethane (DCM). In the step 5, compound 7 was synthesized in good yields by the polymerization of 6 with ARM-PEG20K-SCM. Finally, the target compound 8 was obtained in moderate yield by the condensation of 7 with polypeptide A6. It was important noting that the synthetic and after-treatment procedure was simple, easy and economical, which was conducive to the industrial production. The structures of the compounds 5, 6, 7 and 8 were then confirmed by the 1H NMR/13C NMR and mass spectrometry (MS) (Figs. S1-1–S1-15, Part 1 of Supplementary Data), while their synthetic pro- cedure and experimental data were described in reference.

 

In vivo antiproliferation assays were carried to evaluate the anti- tumor activity of 8, according to the previous literature.27 The MIA PaCa-2 (human pancreatic cancer cell), NCI-H446 (human small cell lung cancer cell line), MDA-MB-231 (human breast cancer cell), HT-29 (human colon cancer), and NCI-N87 (human gastric carcinoma cell) xenograft models were selected in this assay, while irinotecan and BGC0222 were used as positive controls for comparison. The female Balb/c nude mice were randomly divided into the vehicle control group, the 8-treated group and two positive control groups. These four mice groups were treated with saline, irinotecan, BGC0222 and 8 in the same condition, respectively, and each group consisted of 6 tumor- bearing mice. The tumor size was determined twice weekly in two di- mensions and the volume was measured. Relative tumor increment rates (T/C) values and inhibitory rates on the growth of tumor weight were determined. Generally, lower T/C values and bigger inhibitory rates indicated better in vivo antitumor activity.

 

In the MIA PaCa-2 xenograft assay, as shown in Fig. 1A, irinotecan (at the 20 mg/kg dose), BGC0222  (at the 6 mg/kg dose) and 8  (at the   6 mg/kg dose) exhibited significant inhibition on the tumour growth, with T/C values of 49.7%, 16.3% and 2.5%, respectively. Evidently, 8 exhibited the lowest T/C value and consequently better antitumor effect than irinotecan and BGC0222 at the same condition in this mouse model. The tumors were harvested and weighted on day 22, and the inhibitory rates on the growth of tumor weight were then counted.  Fig. 1B showed that 8 showed significant antitumor activity in the MIA PaCa-2 model with an inhibitory rate of 97.7% (P < 0.01), much greater than that of BGC0222 (71.8%, P < 0.01)  and  irinotecan  (47.0%, P < 0.01), also indicating that 8 exhibited the highest anti- tumor effect. It was very important to note that the tumors of two mice even completely subsided and disappeared with the treatment of 8 for 21 days (Fig. 1D), demonstrating good antitumor activity of 8. In ad- dition, no significant change in body weight and no other adverse ef- fects were observed among the mice treated with 8, suggesting that 8 exhibited no significant toxicity to the mice within the period of treatment (Fig. 1C). On the basic of the above observation, it could be concluded that 8 should be a good candidate for antitumor agent. The result seriously proved our expectation that introduction of PEG and chained A6 to irinotecan (replacement of cRGD with chained A6) may lead to increased antitumor activity.

 

In the NCI-H446 xenograft assay, irinotecan (at the 20 mg/kg dose), BGC0222 (at the 6 mg/kg dose) and 8 (at the 6 mg/kg dose) also displayed important inhibition on the tumour growth (Fig. S2-1A, Part 2 of Supplementary Data). The T/C values of irinotecan, BGC0222 and 8 were found to be 62.8%, 40.2% and 3.5%, respectively. It was ob- vious that 8 showed the lowest T/C value and the best antitumor effect in this mouse model. The inhibitory rates assays results (Fig. S2-1B) indicated that 8 showed good antitumor activity in the NCI-H446 model with an inhibitory rate of 77.4% (P < 0.01), greater than that of BGC0222 (43.2%, P < 0.01) and irinotecan (26.8%%, P < 0.01),
showing that 8 exhibited the highest antitumor effect among these three compounds. It was worth noting that the tumor of a mouse completely subsided and disappeared  with  the  treatment  of  8  for 21 days (Fig. S2-1D), indicating good antitumor activity of 8. Moreover, no significant change in body weight and no other adverse effects were found among the mice treated with 8, implying that 8 may exhibit no significant toxicity to the mice within the period of treatment (Fig. S2- 1B). These results indicated that 8 should be good candidate for anti- tumor effect. This result also proved our expectation that introduction of PEGylation and chained A6 to irinotecan (replacement of cRGD with chained A6) may lead to increased antitumor activity, consistent with that in MIA PaCa-2 xenograft assay.
In the MDA-MB-231 xenograft assay (Fig. S2-2A), irinotecan (at the 20 mg/kg dose, T/C value 34.0%), BGC0222 (at the 6 mg/kg dose, T/C value 21.6%) and 8 (at the 6 mg/kg dose, T/C value 1.0%) showed significant antiproliferation on the tumour growth, while 8 exhibited the lowest T/C value and consequently the best antitumor effect in this mouse model. The tumors were harvested and weighted on day 21 (Fig. S2-2D), and the inhibitory rates on the growth of tumor weight were determined. As shown in Fig. S2-2C, 8 (at the 6 mg/kg dose) showed important antitumor activity in the MDA-MB-231 model with an in- hibitory  rate   of   98.8%,   greater   than   that   of   irinotecan   (68.3%, P < 0.01) and BGC0222 (77.3%, P < 0.01), showing that 8 exhibited higher antitumor effect than irinotecan (at the 20 mg/kg dose) and BGC0222 (at the 6 mg/kg dose) in the MDA-MB-231 mouse model. It was worth to noting that no significant change in body weight and no other adverse effects were observed among the mice treated with 8, indicating that 8 exhibited no significant toxicity to the mice within the period of treatment (Fig. S2-2B). These results indicated that 8 should be good candidate for potential antitumor agents, in comparison with irinotecan and BGC0222.

 

In the HT-29 xenograft assay (Fig. S2-3A), irinotecan (at the 40 mg/ kg dose, T/C value 49.0%), BGC0222 (at the 20 mg/kg dose, T/C value 22.7%) and 8 (at the 20 mg/kg dose, T/C value 5.4%) showed clear inhibition on the tumour growth, while 8 displayed the lowest T/C value and consequently the best antitumor effect in this mouse model. The inhibitory rates results (Figs. S3C and S3D) showed that 8 (at the 20 mg/kg dose) showed significant antitumor activity in the HT-29 model with an inhibitory rate of 95.2%, greater than that of BGC0222 (70.2%, P < 0.01) and irinotecan (56.4%), demonstrating that 8 ex- hibited higher antitumor activity than BGC0222 (at the 20 mg/kg dose) and irinotecan (at the 40 mg/kg dose) in the HT-29 mouse model. In addition, no significant change in body weight and no other adverse effects were observed among the mice treated with 8, showing that 8 exhibited no significant toxicity to the mice within the period of treatment (Fig. S2-3B). These results also indicated that 8 should be a good candidate for potential antitumor agents, consistent with that in MDA-MB-231 xenograft assay.

 

The in vivo antitumor activity of 8 was also studied in the NCI-N87 mouse model (Fig. S2-4). The T/C values of irinotecan (at the 60 mg/kg dose), BGC0222 (at the 20 mg/kg dose) and 8 (at the 20 mg/kg dose) were determined to be 40.3%, 26.0% and 11.6%, respectively (Fig. S2- 4A), while their inhibitory rates were counted to be 91.2%, 83.5% and 65.6% (Fig. S2-4C). It was evident that 8 showed the best antitumor activity in this model. Notably, no significant change in body weight and no other adverse effects were observed among the mice treated with 8 (Fig. S2-4B), indicating that 8 showed no significant toxicity to the mice within the 21-day period of treatment and could be a good candidate for potential antitumor agent.

 

In conclusion, we have designed and synthesized a novel PEG-A6-conjugated irinotecan derivative 8 as antitumor agent. The in vivo an- titumor activity assays indicated that 8 exhibited better antitumor ac- tivity than irinotecan and BGC0222 in MIA PaCa-2, NCI-H446, MDA- MB-231, HT-29 and NCI-N87 xenograft models, while no significant change in body weight and no other adverse effects were observed, indicating 8 may be a good candidate for antitumor drug. The above results demonstrated that the rational design of 8 as novel antitumor agent by the modification of irinotecan with PEG and chained A6 was feasible.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influ- ence the work reported in this paper.

 

Acknowledgments
This study was supported by the National Natural Science Foundation of China (No. 21501032), the Innovative Team & Outstanding Talent Program of Colleges and Universities in Guangxi (2017-38), Guangxi Natural Science Foundation (No. 2016GXNSFAA380300) and Guangxi New Century Ten, Hundred and Thousand Talents Project ([2017]42).

 

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