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. 2008 Sep-Oct;5(5):776-86.
doi: 10.1021/mp800019g. Epub 2008 Sep 4.

Novel HPMA copolymer-bound constructs for combined tumor and mitochondrial targeting

Vaikunth Cuchelkar  1 , Pavla Kopecková, Jindrich Kopecek
Affiliations

Novel HPMA copolymer-bound constructs for combined tumor and mitochondrial targeting

Vaikunth Cuchelkar et al. Mol Pharm. 2008 Sep-Oct.

Abstract

A wide variety of therapeutic agents may benefit by specifically directing them to the mitochondria in tumor cells. The current work aimed to design delivery systems that would enable a combination of tumor and mitochondrial targeting for such therapeutic entities. To this end, novel HPMA copolymer-based delivery systems that employ triphenylphosphonium (TPP) ions as mitochondriotropic agents were developed. Constructs were initially synthesized with fluorescent labels substituting for drug and were used for validation experiments. Microinjection and incubation experiments performed using these fluorescently labeled constructs confirmed the mitochondrial targeting ability. Subsequently, HPMA copolymer-drug conjugates were synthesized using a photosensitizer mesochlorin e 6 (Mce 6). Mitochondrial targeting of HPMA copolymer-bound Mce 6 enhanced cytotoxicity as compared to nontargeted HPMA copolymer-Mce 6 conjugates. Minor modifications may be required to adapt the current design and allow for tumor site-specific mitochondrial targeting of other therapeutic agents.

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Figures

Figure 1
Figure 1
Construct design for mitochondrial targeting.
Figure 2
Figure 2
Synthetic scheme for polymer precursor containing disulfide bonds (P-SS-OSu).
Figure 3
Figure 3
Synthetic scheme for (5-carboxypentyl)triphenylphosphonium bromide 4-nitrophenyl ester (TPP-HA-ONp).
Figure 4
Figure 4
Synthetic scheme for P-SS-TPP–lysine–BODIPY.
Figure 5
Figure 5
Synthetic scheme for P-SS-TPP–lysine–Mce6.
Figure 6
Figure 6
Microinjection of TPP–lysine–BODIPY in SKOV-3 cells. In these images, the first field (A) shows the fluorescence due to BODIPY and therefore indicates the subcellular location of TPP–lysine–BODIPY. The second field (B) indicates the fluorescence due to Mitotracker and indicates the intracellular localization of the mitochondria. The third field (C) is the combined image of fields A and B.
Figure 7
Figure 7
Incubation of SKOV-3 cells with TPP–lysine–BODIPY. SKOV-3 cells were initially labeled with Mitotracker Orange and then incubated with 5 μM TPP–lysine–BODIPY. Subcellular fate of TPP–lysine–BODIPY constructs was followed every 15 min for 4 h. In these images, the first field (marked BODIPY) shows the fluorescence due to BODIPY and therefore indicates the subcellular location of TPP–lysine–BODIPY. The second field (marked Mitotracker) indicates the fluorescence due to Mitotracker and indicates the intracellular localization of the mitochondria. The third field (marked Combined) is the combined image of the two fields.
Figure 8
Figure 8
Incubation of SKOV-3 cells with P-SS-TPP–lysine–BODIPY. SKOV-3 cells were initially labeled with Mitotracker Orange and then incubated with 20 μM P-SS-TPP–lysine–BODIPY. Subcellular fate of TPP–lysine–BODIPY constructs was followed every 60 min for 12 h. In these images, the first field (marked BODIPY) shows the fluorescence due to BODIPY and therefore indicates the subcellular location of TPP–lysine–BODIPY. The second field (marked Mitotracker) indicates the fluorescence due to Mitotracker and indicates the intracellular localization of the mitochondria. The third field (marked Combined) is the combined image of the two fields.
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