Table 5.
List of Hierarchical Levels and “Elementary” Steps (Modular Units) Relevant to Drug Delivery and Cancer Therapy with Corresponding Quantitative Models
| Hierarchy | “Elementary” Phenomena and Models | Description and Reference(s) |
|---|---|---|
| Drug and polymer | Molecular level properties of drugs (small molecule species, macromolecular drugs, gene vectors, imaging agents): structure, solubility in water and lipid environments, adsorption | In References 413–416 |
| Molecular level properties of constitutive delivery polymers | In Reference 417 | |
| Modeling of associative (self-assembling) properties of drugs and polymers | In Reference 418 | |
| Transport properties of drugs via lipid structures | In Reference 419 | |
| Transport (controlled-release) properties of polymeric-drug superstructures, including hydrogel constructs | In Reference 420 | |
| Molecular modeling of in vitro receptor–ligand interaction | In Reference 421 | |
| Subcellular | Genetic control model | In References 422,423 |
| “Elementary” model of cancer metabolism | In References 424–429; cancer stem cells430–431a | |
| Signaling pathway models | In References 411,431b,432–437 | |
| Models of nanovehicle uptake, trafficking, degradation, and efflux | Analytical model of nanovehicle diffusion, adsorption, desorption, and endocytosis;438 ligand-induced internalization439,440 | |
| Cellular | Nutrient and oxygen effects | Compartmental (subcellular) analysis of nutrient influx and efflux441 |
| Radiation response | In References 442,443 | |
| Response to chemotherapy | In References 444–446 | |
| Models of combination therapy | In References 447–449 | |
| Models of cell cycle | In Reference 450 | |
| Models of tumor invasion and metastasis | In References 451,452 | |
| Models of hematopoiesis | In Reference 453 | |
| Capillary network growth | In References 454,455 | |
| Models of cell growth, quiescence, and apoptosis | In References 456–458a | |
| Models of nanovehicle/cell interaction; ligand-mediated targeting models | In;458b magnetic nanovehicle transport and capture;459 Folate targeting of liposomes;460 optimal tumor targeting by antibodies461 | |
| Multicellular/Tissue | Nutrient and vehicle/drug transport; convective interstitial transport | Tumor blood perfusion and oxygen transport;462 vascular transport—permeable versus nonpermeable capillaries;463 tumor spheroid penetration by antibody;464 hypoxia model;465 interstitial transport466 |
| Interaction with RES | In Reference 467 | |
| Interaction with immune system | In Reference 468 | |
| Interaction within the vascular system (EPR effect) | In Reference 469 | |
| Interaction with hematopoietic system | In Reference 453 | |
| Interaction with lymphatics | In Reference 471 | |
| Physiologically-based pharmacokinetic models: compartmental analysis and biodistribution | Tumor uptake of antibodies: compartmental analysis;471,472 first-pass model;473–476 pharmacokinetic cancer mode133 | |
| Systems model | Solving large-scale, multi-scale metabolic and signaling models coupled with upper system boundary conditions | Dynamic cancer network inference model476–478; network model479 |
| Cancer as a systems disease | The most comprehensive models yet available, still very far from ideal situation412,480,481 | |
| Cancer systems diagnostics | In Reference 482 | |
| Cancer systems epidemiology | In Reference 483 | |
| Bottlenecks in big Pharma and Biotech industries: discovery and development | Systems biology in drug discovery484 |
The information flow is mostly linear from lower levels to the upper ones, although a forward feedback may occur between the “Drug and polymer” and “Multicellular/Tissue” levels. Note, only very few entries (references) were selected to demonstrate tools are available.