Nonlinear Amplification Phenomenon Nanomedicine Dose Characteristic Signal Role of Nanomedicine Dose Hormesis Low dose as mild stressor Depends on interaction with organism more than on specific pharmacological nature of stressor/agent Able to initiate adaptive response Low dose evokes response in opposite direction to that for high dose. Cross-adaptation between chemically-unrelated stressors/agents observed. Nanoparticles can evoke hormesis. Time-Dependent Sensitization (TDS) Low dose as danger signal Pulsed dose administration (repeated intermittent timing) Salient threat or stressor for the system Passage of time between discrete doses leads to progressive growth of host response to next dose. Overly frequent doses will cause sequential oscillatory reversals in direction of response from dose to dose. Cross-sensitization between chemically-unrelated stressors/agents observed. Homeopathic medicines can initiate and elicit TDS. Stochastic Resonance (SR) Low dose as signal Concomitant background noise present (systemic biology of the organism-wide emergent disease process) Salient signal for the system Host response amplification in response to the weak signal value of the low dose by the background noise in the system. SR in animal sensory systems for detecting approach of a dangerous predator observed. SR between two quantum dot (small NPs) and with carbon nanotubes or metal NPs observed.

Table 2: Proposed low dose effects: mediating processes for therapeutic effects from pulsed low doses of nanomedicines in a complex adaptive system. Amplification phenomena depend on nonlinear interactions with the dynamics of the organism as a complex adaptive system.