Polymeric micelles in anticancer therapy: targeting, imaging and triggered release

Abstract

Micelles are colloidal particles with a size around 5-100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward.

Fig. 1

Schematic drawing of polymeric micelle (a). Micelle conjugated with a targeting ligand (b). Micelle containing an incorporated contrast agent or chelated imaging moieties (c). Micelle modified for triggered drug release (d). Either the hydrophilic or hydrophobic polymer can be rendered thermo/pH/light/ultrasound-sensitive. Optimized micelle for anticancer therapy, bearing targeting ligands, contrast agents or imaging moieties, therapeutic drugs and polymers suitable for triggered, controlled release (e).

Fig. 2

Schematic structure of NK012, consisting of PEG and partially modified polyglutamate. PEG is used to form the hydrophilic segment, and SN-38 was incorporated into the hydrophobic core of the micelle (33). Reproduced with permission from the American Association for Cancer Research.

Fig. 3

Tumor volume growth in a nude mice xenograft model after i.v. administration of free doxorubicin, doxorubicin-loaded PLGA-b-PEG micelles and doxorubicin/folate PLGA-b-PEG micelles (65). Reproduced with permission from Elsevier.

Fig. 4

TEM image of SPION-loaded micelles containing 1 mg/mL SPIONs, and 0.9 mg/mL mPEG-b-p(HPMAm-Lac2) at high magnification (84). Reproduced with permission from the American Chemical Society.

Fig. 5

Schematic model of the ‘pop-up’ mechanism-based micelle formulation. The carrier system consists of two components, a PLLA-b-PEG micelle conjugated to TAT and a pH sensitive diblock polymer PSD-b-PEG. At normal blood pH, the sulfonamide groups are negatively charged, binding via electrostatic interactions to the TAT units, thereby shielding these groups (a). When the system experiences a decrease in pH (near tumor) sulfonamide looses charge and detaches, thus exposing TAT for interaction with tumor cells (b) (183). Reproduced with permission from Elsevier.

Fig. 6

MicroSPECT/CT images illustrating the whole-body biodistribution of the non-targeted block copolymer micelles (NT-BCM) and targeted block copolymer micelles (T-BCM) labeled with ¹¹¹In, in MDA-MB-468 tumor-bearing mice that were injected intravenously at a dose of 250 mg/kg of PEG-b-PCL copolymer. The maximum intensity projection and the tumor transverse slice images were acquired at 48 h post injection. The tumor transverse slices shown represent consecutive sections of the tumor at an approximate thickness of 4 mm/section (77). Reproduced with permission from Elsevier.