Thermosensitive liposomes for localized delivery and triggered release of chemotherapy

Abstract

Liposomes are a promising class of nanomedicine with the potential to provide site-specific chemotherapy, thus improving the quality of cancer patient care. First-generation liposomes have emerged as one of the first nanomedicines used clinically for localized delivery of chemotherapy. Second-generation liposomes, i.e. stimuli-responsive liposomes, have the potential to not only provide site-specific chemotherapy, but also triggered drug release and thus greater spatial and temporal control of therapy. Temperature-sensitive liposomes are an especially attractive option, as tumors can be heated in a controlled and predictable manner with external energy sources. Traditional thermosensitive liposomes are composed of lipids that undergo a gel-to-liquid phase transition at several degrees above physiological temperature. More recently, temperature-sensitization of liposomes has been demonstrated with the use of lysolipids and synthetic temperature-sensitive polymers. The design, drug release behavior, and clinical potential of various temperature-sensitive liposomes, as well as the various heating modalities used to trigger release, are discussed in this review.

Fig. 1

Examples of current nanomedicines: (A) liposomes, (B) micelles, (C) polymeric nanoparticles, (D) dendrimers, (E) carbon nanotubes, and (F) polymer-drug conjugates.

Fig. 2

Schematic representation of a liposome. Single lipid units such as the phospholipid examples shown to the right form a stable bilayer around an aqueous inner core.

Fig. 3

Possible mechanisms involved in combination hyperthermia and thermosensitive liposome therapy: (A) drug-loaded liposomes (green indicating the lipid shell and yellow indicating the drug) preferentially extravasate from pores in leaky tumor blood vessel walls (i.e. EPR effect), (B) applied mild hyperthermia (hyperthermia region indicated by red circle) increases tumor vessel pore size, increasing tumor liposome extravasation, (C) hyperthermia triggers drug release from temperature sensitive liposomes in the tumor vasculature as well as in (D) the tumor interstitium. Recent findings suggest the mechanism of drug delivery from combination TSL and HT is dominated by intravascular release (C) [62].

Fig. 4

Temperature-dependent phase transition of a lipid bilayer. An increase in the lipid bilayer fluidity due to an increase in temperature above T_c is associated with an increase in drug release.

Fig. 5

Schematic of the lysolipid-containing thermosensitive liposomes (LTSL) developed by Needham, Dewhirst et al. [94]. Lipid bilayers are composed of DPPC and MPPC (10 mol%), a lysolipid that stabilizes grain boundary defects during the phase transition, leading to rapid drug release.

Fig. 6

Proposed mechanisms of drug release from traditional thermosensitive liposomes (TTSL) and the lysolipid-containing thermosensitive liposomes (LTSL) developed by Needham, Dewhirst et al. [94]. Upon heating, grain boundaries form between solid and liquid domains. Melting is initiated at these boundaries, leading to drug release. In LTSL, lysolipids such as MPPC accumulate at these boundaries and form stabilized defects, leading to enhanced drug release.

Fig. 7

Illustration of drug release from polymer-modified thermosensitive liposomes (PTSL). At temperatures greater than the lower critical solution temperature (LCST) of the polymer, polymer chains collapse, resulting in disruption of the membrane and release of encapsulated drug.

Fig. 8

Schematic of fixation of polymer chains having anchors at (A) random positions on the polymer backbone and (B) the chain end to a liposome membrane.

Fig. 9

Copolymers of NIPAAm and (A) N-acryloylpyrrolidine (Apr), (B) N,N-dimethylacrylamide (DMAM), and (C) N-isopropylmethacrylamide (NIPMAM) discussed in [117]. Two dodecyl groups at the terminal end of the chains allow fixation to the hydrophobic core of the lipid membrane. Copolymers presented similar LCST (~40 °C) but varying transition enthalpies (Apr < DMAM < NIPMAM). Drug release from polymer-modified liposomes increased with increasing ΔH.

Fig. 10

Structure of p(NIPAAm-co-PAA) synthesized via RAFT chemistry [102]. The dual-sensitive polymer (temperature, pH) was fixated onto liposomes, and drug release triggered by both heating and acidic pH. The pH-sensitivity is applicable to cancer therapy, as tumors are known to be slightly acidic.

Fig. 11

Structure of p(EOEOVE-s-ODVE) synthesized via living cationic polymerization [118,123,124].

Fig. 12

Structure of pluronic F-127. Hydrophilic polyethylene oxide blocks flank the hydrophobic polypropylene block. The polymer forms micelles at elevated temperatures, and when encapsulated in liposomes can disrupt the lipid membrane, providing a means of temperature-triggered release [125,127].

Fig. 13

Schematic of interstitial hyperthermia showing single radiofrequency probe with expandable prongs for more uniform heating.

Fig. 14

The development of MR-compatible focused ultrasound transducers has led to the emergence of MR-guided focused ultrasound as a very effective tool for image-guided thermal therapy. Focused ultrasound transmitted through the skin can heat tumors rapidly (i.e. heating in less than a second) without damaging intervening tissue. Two-dimensional maps of ultrasound-mediated heating are possible with MR thermometry, thus allowing for feedback control of the focused ultrasound system. The image-guided system can be used for sustained, controlled heating of tumors above the threshold for triggered release of chemotherapeutics from thermosensitive liposomes.