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

Oerlemans C, Bult W, Bos M, Storm G, Nijsen JF, Hennink WE - Pharm. Res. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, University Medical Center, Heidelberglaan 100, Utrecht, The Netherlands. C.Oerlemans@umcutrecht.nl

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.

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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.
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Fig6: 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.

Mentions: Another combination of strategies in micelle-based drug delivery is active targeting and imaging. In this way, the micelles can be tracked throughout the body, and the micelle deposition at the target site can be determined. Rossin et al. tracked the biodistribution of poly(acrylic acid-b-methyl acrylate) (PEG-b-PAA-b-PMA) shell cross-linked micelles (SCKs) with autoradiography of the 64Cu-labeled micelles, but did not find any significant higher uptake of folate-conjugated micelles compared to non-targeted micelles in KB tumor cell xenograft-bearing mice. This was ascribed to the presence of necrotic areas in big, fast-growing tumors, which hampered extravasation of the micelles into tumor tissue (187). However, folate receptor-mediated uptake of the SCKs in very small tumors was observed, suggesting the possible use of radiolabeled SCKs as drug delivery systems for imaging and treatment of early-stage tumors. EGF-receptor-targeted PEG-b-PCL micelles labeled with 111In were developed by Lee et al. (77). Images taken with micro-SPECT/CT showed that the intratumoral distribution of both targeted and non-targeted micelles was heterogeneous and positively correlated with tumor vascularization. Enhanced accumulation in tumor tissue was observed with the targeted micelles (T-BCM) compared to non-targeted micelles (NT-BCM) (Fig. 6). In a recent in vitro study, Guthi et al. described a multifunctional methoxy-terminated PEG-b-PDLLA micelle system that is encoded with a lung cancer-targeting peptide (LCP) and loaded with SPIONs together with doxorubicin for MR imaging and therapeutic delivery, respectively (188). A significantly increased cell targeting, micelle uptake, superb T2 relaxivity for ultrasensitive MR detection and cell cytotoxicity in αvβ6-expressing lung cancer cells were shown. Previously, the same micelles were conjugated with a cRGD ligand that can target αvβ3 integrins on tumor endothelial (SLK) cells (189), resulting in ultrasensitive detection by MRI and growth inhibition of tumor SLK cells. Hong et al. prepared a micellar formulation consisting of folate-conjugated PEG-b-PCL loaded with doxorubicin and SPIONs. In vitro studies with human hepatic carcinoma cells (Bel 7402 cells, which overexpress surface receptors for folic acid) showed a significant inhibition in proliferation compared to non-targeted micelles (190). Moreover, MR imaging revealed detection of the targeted micelles in the cells. These studies indicated the advantages of image-guided drug delivery. Diagnostics are considerably improved and drug delivery efficiency is significantly enhanced by the combination of active tumor targeting and imaging. Table VII summarizes the micellar formulation characteristics combining different approaches.Fig. 6


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

Oerlemans C, Bult W, Bos M, Storm G, Nijsen JF, Hennink WE - Pharm. Res. (2010)

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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2982955&req=5

Fig6: 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.
Mentions: Another combination of strategies in micelle-based drug delivery is active targeting and imaging. In this way, the micelles can be tracked throughout the body, and the micelle deposition at the target site can be determined. Rossin et al. tracked the biodistribution of poly(acrylic acid-b-methyl acrylate) (PEG-b-PAA-b-PMA) shell cross-linked micelles (SCKs) with autoradiography of the 64Cu-labeled micelles, but did not find any significant higher uptake of folate-conjugated micelles compared to non-targeted micelles in KB tumor cell xenograft-bearing mice. This was ascribed to the presence of necrotic areas in big, fast-growing tumors, which hampered extravasation of the micelles into tumor tissue (187). However, folate receptor-mediated uptake of the SCKs in very small tumors was observed, suggesting the possible use of radiolabeled SCKs as drug delivery systems for imaging and treatment of early-stage tumors. EGF-receptor-targeted PEG-b-PCL micelles labeled with 111In were developed by Lee et al. (77). Images taken with micro-SPECT/CT showed that the intratumoral distribution of both targeted and non-targeted micelles was heterogeneous and positively correlated with tumor vascularization. Enhanced accumulation in tumor tissue was observed with the targeted micelles (T-BCM) compared to non-targeted micelles (NT-BCM) (Fig. 6). In a recent in vitro study, Guthi et al. described a multifunctional methoxy-terminated PEG-b-PDLLA micelle system that is encoded with a lung cancer-targeting peptide (LCP) and loaded with SPIONs together with doxorubicin for MR imaging and therapeutic delivery, respectively (188). A significantly increased cell targeting, micelle uptake, superb T2 relaxivity for ultrasensitive MR detection and cell cytotoxicity in αvβ6-expressing lung cancer cells were shown. Previously, the same micelles were conjugated with a cRGD ligand that can target αvβ3 integrins on tumor endothelial (SLK) cells (189), resulting in ultrasensitive detection by MRI and growth inhibition of tumor SLK cells. Hong et al. prepared a micellar formulation consisting of folate-conjugated PEG-b-PCL loaded with doxorubicin and SPIONs. In vitro studies with human hepatic carcinoma cells (Bel 7402 cells, which overexpress surface receptors for folic acid) showed a significant inhibition in proliferation compared to non-targeted micelles (190). Moreover, MR imaging revealed detection of the targeted micelles in the cells. These studies indicated the advantages of image-guided drug delivery. Diagnostics are considerably improved and drug delivery efficiency is significantly enhanced by the combination of active tumor targeting and imaging. Table VII summarizes the micellar formulation characteristics combining different approaches.Fig. 6

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, University Medical Center, Heidelberglaan 100, Utrecht, The Netherlands. C.Oerlemans@umcutrecht.nl

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.

Show MeSH
Related in: MedlinePlus