Thermosensitive Systems

In addition to ultrasonication, micelles can also be designed to trigger the release of drugs at the tumors using heat as an external stimulus. Application of thermo-responsive micelles for the treatment of solid tumors involves the use of a thermosensitive polymer as the micelle-building block and the local administration of heat at the tumor site. Thermo-responsive copolymers including poly(N-isopropylacrylamide-b-D,L-lactide) (PIPAAm-b-PDLLA), poly(N-isopropylacry-lamide-b-(butyl methacrylate)) (PIPAAm-b-PBMA), poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-poly(D,L-lactide-co-glycolide) (P(IPAAm-co-DMAAm)-b-PLGA) have

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been used for the preparation of thermo-responsive micelles. , These micelles undergo reversible structural changes that facilitate drug release above the lower critical solution temperature (LCST) of the thermosensitive polymer. In the case of PIPAAm micelles, dehydration of the outer shells of the micelles also occurs above the LCST, resulting in the enhanced adsorption of drug-loaded micelles to cells via increased hydrophobic interactions.155-157

Okano's group developed a thermo-responsive, doxorubicin-loaded micelle system with an LCST of 32°C. By toggling the temperature below and above the LCST, the release of doxorubicin may be switched reversibly between an on and off state. At temperatures above the LCST, doxorubicin release is accelerated, whereas decreasing the temperature to levels below the LCST results in minimal drug release.155 This effect is also influenced by the state of the micelle core in addition to the thermosensitivity of the PIPAAm outer shells. For instance, micelles that are formed from copolymers with liquid-like cores (e.g., Tg = 20°C for PBMA) are more sensitive to thermal triggered drug release than micelles with solid-like cores (e.g., Tg = 100°C for polystyrene (PS)) at temperatures above the LCST. As a result, the doxorubicin-loaded PPIAAm-b-PBMA micelles were three times more cytotoxic than the PPIAAm-b-PS micelles above the LCST mainly as a result of their distinct doxorubicin release profiles. At temperatures below the LCST, both systems exhibited almost no cytotoxicity.153

For in vivo delivery, the LCST of the thermo-responsive micelles should be several degrees above physiological temperature (i.e., LCSTO 37°C).157 The LCST can be manipulated by fine-tuning the hydrophilicity of the PIPAAm segment. The addition of hydrophilic groups to the

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PIPAAm polymer can elevate the LCST of the micelles formed. , For example, Liu et al. reported that by adding hydrophilic DMAAm to the PIPAAm segment, the P(IPAAm-co-DMAAm)-b-PLGA micelles have an LCST of approximately 39°C. As a result, the doxorubici-n-loaded P(IPAAm-co-DMAAm)-b-PLGA micelles have been shown to be more potent in the 4T1 mouse breast cancer cells at 39.5°C (IC50 = 3.1 mg/L) than at 37°C (IC50 = 7.9 mg/L).122 Therefore, heat-activated drug release in tumors (above 37°C) can reduce the possible toxicity associated with the drug in healthy tissues (at 37°C).

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