Figure 10.

Image-guided modeling of controlled NP drug release and multistage NP design. (A-C) Conventional two-stage NP delivery systems consist of a nano-carrier and its drug payload (top), while multi-stage systems consist of the primary nano-carrier, a secondary NP, and the drug payload (A). Multi-stage strategies lead to complex changes in how NP parameters relate to overall efficacy, for instance as modeled by cancer cell killing as a function of two parameters (B): NP binding rate constant to target cells, and the drug release rate. Such analysis suggests that the multistage design may be particularly effective under certain parameter combinations (boxed outline), and multistage NP behaviors can be visualized by imaging to quantify improved tumor penetration in a fibrosarcoma xenograft characterized by high MMP2 expression (C; scale bar, 100 μm; Adapted with permission from ¹⁷⁷, ¹⁷⁸, copyright 2011, 2015 National Academy of Sciences, U.S.A., Springer Nature). (D-E) Simultaneous imaging of nano-carriers and their drug payload reveals another example of multistage delivery, whereby NPs are initially taken up by TAMs, which then act as drug reservoirs that release drug payload (here, a DNA-damaging platinum agent) to neighboring cancer cells. (D) Polymeric micelle TNP were labeled with two fluorophores, such that the polymer vehicle and cytotoxic cisplatin-related payload could be simultaneously imaged. The DNA damage response marker 53BP1 was used to correlate local drug exposure to response (Scale bar, 50 μm). (E) Flow cytometry of excised xenograft tumors showed that cancer cells have more drug payload than TAM, relative to the corresponding amount of NP vehicle in each cell, which combined with imaging (D) indicates that payload redistributed from TAM to tumor cells (Adapted with permission from ³¹, copyright 2015 Springer Nature).