br mm in the BC LMNs
40.8 ± 5.4 mm3 in the BC/LMNs + M + L group (TGI: 80.38%). Due to the FA receptor/magnetic/laser multi-targeting capability of LMNs, the tumor growth was eﬀectively inhibited. Therefore, LMNs and BC/ LMNs have a great potential to be used as powerful agents for in vivo chemotherapy and PDT in breast cancer treatment.
We evaluated the in vivo biocompatibility of LMNs by body weight changes (Fig. 5C middle) and living rate. No significant weight loss can be found, and the body weight increased in the control at approxi-mately the same rate as the LMNs injected group. The survival results of rat correlated to the therapy response were observed in Fig. 5C (right). Compared to other groups, the LMNs + M + L group showed improved survival significantly in 14 days. The immunohistochemical analysis (Fig. 5D) revealed reduced light brown staining in LMN group when compared to the control group, indicating that the expression of Ki67 and Bcl-2 decreased after LMN administration, which further supported the results of the in vitro experiments.
In enrichment of LMNs in the tumor and skin tissues are visually observed using Prussian blue staining. As shown in Fig. 6A and B, the iron levels significantly increase in the tumors treated with LMNs or BC/LMNs with a magnetic field and laser, which are much more than that in tumors treated by LMNs without magnetic fields. The Prussian blue staining assay confirms the targeted tumor accumulation of the transdermal administered LMNs, which facilitated the selective tumor ablation and a reduction in the adverse eﬀects to normal tissues. As shown in Fig. 6C, we have characterized the distribution of the LMNs in tumor, the applied skin, and major organs by ICP. The results shown that the LMNs were significantly enriched in the tumor tissues.
HE staining of various tissues revealed that there were no patho-logical eﬀects in various organs, such as kidney, liver, spleen, heart, or
lung (Fig. 6D). These results provide evidence for the hypothesis that LMN injection does not produce any significant side eﬀects in mice and its administration is beneficial during the course of the experiments. Meanwhile, HE staining of tumor slices in the LMNs + M + L group and the BC/LMNs + M + L group reveal severe tissue damage and diﬀer-ences in tissue morphology when compared with other groups, with an obvious reduction in the number of proliferating cells.
In order to quantify the toxicity of MHNPs and LMNs, we have detected the assessment of hematologic parameters (Fig. S3C and D). The toxicity in vivo was assessed by counting the white blood Fluxametamide (WBC), blood platelets (PLT), and red blood cells (RBC), respectively. The results of the WBC, PLT, and RBC counts on the 14th day following treatment reveals no evidence of leukopenia or associated toxicity (Fig. 6E). The tolerance study with magnetic nanoparticles was per-formed in mice and shows no significantly changes in the hematological and biochemical profiles as well as no organomegaly appearances can be observed after injection or transdermal of LMNs.
There is a high degree of diversity between and within tumors, in addition to among patients, which interact to determine the risk of disease progression and therapeutic resistance. Advanced technologies such as whole-genome sequencing, proteomic technology screening currently allow researchers to analyze tumors at ground breaking scales. However, translating the research achievement into clinical practice remains challenge, partly due to the tumor heterogeneity driven by the diversity of the diﬀerent cancer cells and their micro-environments [37–40].
Tumors are often repeat attack because of heterogeneity. Moreover, because of cells survive and continue to grow after once administration, nanoparticles have to be reinjected to achieve a right amount of med-ication within the tumors for continuous cancer treatments. However, frequent and multiple injections of nano-drugs may cause some un-certain side eﬀects and leading to patient discomfort. By combining chemotherapy and photodynamic therapy, the broad-spectrum killing eﬀect on the tumor is greatly enhanced. Simultaneously, transdermal delivery can increase the acceptance of the mode of administration, reducing the side eﬀects and pain caused by cancer treatment [41,42].
The trans-barrier pathways of the skin are refractive to majority of the molecules particularly those that are hydrophilic. It is essential to breaching the skin surface for purposes of transdermal drugs delivery through the protective barrier. The later transdermal method is give permission for using in disease treatment, whereas nano-sized (5 nm−10 µm) skin perforators like micro needle are still under de-velopment for transdermal drug delivery [43,44]. The BC membrane is comprised of cellulose microfibrils, which are aggregates of semi-crystalline extended cellulose. The BC nanofiber network can load the nanoparticles into the pore of the membrane [43-49].