br Fig In vivo fluorescence
Fig. 5. In vivo fluorescence imaging after administration of Cy7.5-labeled PAMAM and Cy7.5-labeled [email protected] A: saline; B: Cy7.5-labeled PAMAM; C: Cy7.5-labeled
[email protected], Pt-Dox, PAMAM-Pt-Dox, [email protected], and [email protected], respectively. The growth of MDA-MB-231 tumors (Fig. 6a) was measured every 2 days. The results showed that PAMAM-Pt-Dox significantly outperforms the Dox/Pt group in terms of anticancer activity, whereas [email protected] demonstrated a higher anticancer efficiency than other groups. Two days after the last treatment, mice were euthanized, tumors were harvested, and tumor mass (Fig. 6c) and tumor morphology (Fig. 6d) were analyzed. Consistent with the tumor growth curve, a pronounced suppression of tumor growth was observed in the [email protected] group. However, the Pt-Dox-treated group displayed a significant loss in body weight, thus suggesting severe systemic toxicity (Fig. 6b). The above findings were further confirmed by sectioning the tumor and performing histological analysis (Fig. 7). Large nuclei and more Pyocyanin in saline and [email protected] groups were observed, thus demonstrating the powerful ability of tumor cell proliferation. The degree of tumor tissue necrosis in mice that were treated with [email protected] was much higher than that in mice treated with other drug formulations, thus demonstrating the anticancer effect of [email protected]
3.6. In vivo safety evaluation of [email protected]
In this study, the in vivo biosafety of [email protected] was evaluated. Considering that the main side effect of Dox is cardiac damage, we investigated whether [email protected] caused car-diac damage . In brief, tumor-bearing mice were intravenously injected every 2 days with different treatments (Fig. 7) for a total of
6 times. Then, the heart, liver, spleen, lung, and kidneys from mice in each group were removed. Sections were prepared and stained with hematoxylin and eosin for histological analysis. When com-pared with the control group, no significant tissue damage was observed in [email protected] mice (Fig. 7), thus indi-cating that [email protected] was a safe drug delivery carrier for tar-geted tumor therapy.
Because of the anticancer effects of Dox and Pt, combination treatment of Dox and Pt for the treatment of cancer is believed to be the first-line chemotherapy drug in the clinic. However, the co-delivery of Pt and polyaromatic drugs was found to be challeng-ing because of their antagonistic nature and variation in terms of solubility. Therefore, it is important to identify an alternative approach that can prevent this issue. To this end, previous studies have demonstrated great therapeutic effects. For example, Wu et al. developed a new type of uniform stimuli-responsive nanogel and showed that the prepared nanogels exhibited highly effective multidrug resistance against MCF-7/ADR tumors with limited side effects . Li et al. designed a novel type of Pt and Dox co-delivery system based on a modified poly(acrylic acid) mesoporous silica nanoparticles platform, which exhibited significantly more cyto-toxicity on HeLa and A357 cells . Although these strategies have shown to improve the therapeutic effects of Dox and Pt, the targeting and excretion effects from the body remain limited because of the uneven distribution of particle size and limited tumor-targeting efficiency. To overcome these obstacles, PAMAM
Fig. 6. In vivo evaluation of antitumor activity of [email protected], Pt-Dox, PAMAM-Pt-Dox, [email protected], and [email protected] after every other day of i.v. injection for half month at a dose of 10 mg kg 1 in nude BALB/c mice bearing MDA-MB-231 tumors. (a) Relative tumor volumes; (b) curves showing body weight per treatment; (c) relative tumor weight; (d) representative tumors per treatment.
Fig. 7. Histological analysis of the heart, liver, spleen, lung, kidney, and tumors at 14 days post injection of different drugs, saline, [email protected], Pt-Dox, PAMAM-Pt-Dox, [email protected], and [email protected] Sections were stained with H&E and observed under a light microscope. Scale bar: 200 mm.
dendrimers were used as a drug delivery carrier for Dox and Pt because of the virtue of well-controlled molecular structures and unique multivalent co-operativity. As shown in Fig. 1, the prepared [email protected] exhibited an even distribution of nanoparticle size ranging from 20 to 50 nm. Considering that nanoparticles with a size ranging between 20 and 50 nm could easily enter tumors through ERP effects , it could be concluded that [email protected] could enter and accumulate more easily in tumor cells than any other nanoparticle [16,42]. This may be attributed to the fact that HA was used as the targeting group because of its strong affinity to CD44 receptors that were overex-pressed in several tumors [43,44]. The strategy of conjugating HA with nanodrug delivery system has been widely used for the design of nanodrug delivery systems, such as graphene oxide , liposomes , poly(d,l-lactide-co-glycolide) , the effect of which on tumor/cancer has been proved by both in vitro and in vivo studies. Similar results were found in a previous study when PAMAM was used as the nanocarrier for the delivery of topotecan hydrochloride . Another major advantage is that HA is a con-stituent of the human body ; therefore, when HA is used as the targeting group, no cytotoxicity will be induced on the human body.