| Metastatic breast cancer and Pancreatic cancer are the major leading cause of cancer mortality. The benefit of traditional surgery, chemmotherapy and raidotherapy is small, and little progress has been made on the treatment. Although advances in nanomedicine have provided a promising strategy for the drug delivery to most primary solid tumor, the traditional nano-carrier drug delivery systems (NDDS) have provided only modest survival benefits for the patients suffering these two kinds of tumors. Importantly, these drugs have little therapeutic effect on cancer metastasis because of their low accumulation in breast cancer metastasis foci and pancreatic tumor. Small metastases and pancreatic tumor are poorly vascularized and hypoperfused, therefore they are not well accessed by big-sized nanoparticles via the EPR effect. Therefore, alternative methods against these two tumors are necessary.Discribed by some literatures, decreasing the size of nanoparticle statistically significantly increased its tumor vascular permeability, especially in the poorly vascularized and hypoperfused pancreatic tumor, which provides us a new reference to design NDDS against metastatic breast cancer and pancreatic cancer. Here, a small-sized docetaxel-loaded PM DDS (DTX-PM) has been constructed using amphilic copolymer mPEG2000-b-PDLLA1300, whose size is determined as16nm by Dynamic light scattering method and smaller than the NDDS ever reported. Moreover, DTX-PM with a high loading capacity for DTX is very stable and can be easily lyophilized, which is vital for the clinical use. TAT, RGD and NGR peptides were respectively attached to the distal tips of PEG moieties of DTX-PM, which provided us TAT-PM, RGD-PM and NGR-PM with different PM surface characteristics.4T1cell line,4T1luc cell line and Capan-2luc cell line that stably expressed luciferase were used as tumor cell model. Furthermore, we established4T1&4T1luc spontaneous metastasis breast cancer model,4T1luc post-surgery breast cancer therapy model and Capan-2luc orthotopic transplantation model of huaman pancreatic cancer model, which are deemed as patient-like model, was used in the in vivo study. Compared to free-DTX (commercialized product Duopafei(?)), the small-sized DTX-PM was found to be very effective against metastasis in vivo on4T1spontaneous metastatic model and4T1luc post-surgery therapy model, which complied with our hypothesis; however, TAT-PM, RGD-PM and NGR-PM had the poorer performance in4T1metastasis therapy compared to DTX-PM, which reminded us that DTX-PM may block the lymphatic metastasis way rather than attack the small metastases foci. More experiments are needed to prove this underlying mechanism. In the in vivo study for Capan-2luc pancreatic cancer, Duopafei(?) almost failed, while DTX-PM had much better therapeutic effect attributed to its hyperpermeability in the hypoperfused tumor. However, TAT-PM, RGD-PM and NGR-PM all had an equal therapeutic effect with DTX-PM.Accordin to our initial hypothesis, TAT-PM, RGD-PM and NGR-PM shall deserve better therapeutic effects against malignant breast cancer and pancreatic cancer. The unexpected negative result may attribute to the in vivo stability problem of the three small-sized PM. To verify this speculation, we designed two more new NDDSs, whose stablity were further strengthened compared to DTX-PM, but failed us. How to design the new small-sized NDDS with higher in vivo stability will be our focus in the future.As a whole, this study designed a series of small-sized PM loaded with DTX, one of which, DTX-PM show much better therapeutic effect against malignant breast cancer metastasis and pancreatic cancer. Moreover, this study revealed the great potential of small-sized PM in the treatment of malignant breast cancer metastasis as well as pancreatic cancer, which may provide new strategy in the development of nanomedicine for diagnosis and therapy for cancer. |
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