Hyperthermia and Temperature-Sensitive Nanomaterials for Spatiotemporal Drug Delivery to Solid Tumors

Abstract

Nanotechnology has great capability in formulation, reduction of side effects, and enhancing pharmacokinetics of chemotherapeutics by designing stable or long circulating nano-carriers. However, effective drug delivery at the cellular level by means of such carriers is still unsatisfactory. One promising approach is using spatiotemporal drug release by means of nanoparticles with the capacity for content release triggered by internal or external stimuli. Among different stimuli, interests for application of external heat, hyperthermia, is growing. Advanced technology, ease of application and most importantly high level of control over applied heat, and as a result triggered release, and the adjuvant effect of hyperthermia in enhancing therapeutic response of chemotherapeutics, i.e., thermochemotherapy, make hyperthermia a great stimulus for triggered drug release. Therefore, a variety of temperature sensitive nano-carriers, lipid or/and polymeric based, have been fabricated and studied. Importantly, in order to achieve an efficient therapeutic outcome, and taking the advantages of thermochemotherapy into consideration, release characteristics from nano-carriers should fit with applicable clinical thermal setting. Here we introduce and discuss the application of the three most studied temperature sensitive nanoparticles with emphasis on release behavior and its importance regarding applicability and therapeutic potentials.

Keywords: hyperthermia; liposomes; polymeric nanoparticles; temperature sensitive nanoparticles; triggered drug release.

Figure 1

Schematic representation of the effect of mild hyperthermia on drug delivery to tumors. Delivery of non-temperature sensitive nanoparticles (a), or temperature sensitive nanoparticles (b) to tumor is enhanced by application of mild hyperthermia. Mild hyperthermia increases regional blood flow and perfusion, causes vasodilation, and increases vascular permeability, resulting in increased extravasation and more homogeneous distribution of nanoparticles deeper into the tumor. When combined with temperature sensitive nanoparticles the additional advantage is increased cellular delivery of free drug upon release from the nanoparticles in response to heat.

Figure 2

Schematic representation of postulated mechanisms of drug release from different temperature sensitive nanoparticles in response to exposure to hyperthermia (HT). (a) Upon heating of a temperature sensitive liposome (TSL) phospholipids grain boundaries form between coexisting phospholipids of solid-like and liquid-like states from which encapsulated drug releases. Presence of lysolipids stabilizes the grain boundaries leading to ultrafast drug release from the liposome at hyperthermia condition. (b) At temperatures (T) below the release temperature (lower critical solution temperature, LCST) of temperature sensitive copolymers, from which temperature sensitive polymeric nanoparticles (TSPN) have been formed, the outer shell of the nanoparticle consists of fully hydrated and stretched polymers. By increasing the temperature higher, the hydrated outer shell collapses by losing hydrophilicity and becomes hydrophobic which leads to drug release and aggregation of TSPN. (c) Upon heating of liposomes modified with temperature sensitive polymers (TSPL) to temperatures above the LCST, the temperature sensitive motifs of copolymers lose hydrophilic reactions and tend to interact with hydrophobic regions of phospholipid bilayers which results in drug release, aggregation, or disintegration of liposomes.