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. 2012 Mar;12(3):412-22.
doi: 10.1002/mabi.201100340.

Prostate-cancer-targeted N-(2-hydroxypropyl)methacrylamide copolymer/docetaxel conjugates

Jihua Liu  1 , Pavla Kopečková, Huaizhong Pan, Monika Sima, Patrick Bühler, Philipp Wolf, Ursula Elsässer-Beile, Jindřich Kopeček
Affiliations

Prostate-cancer-targeted N-(2-hydroxypropyl)methacrylamide copolymer/docetaxel conjugates

Jihua Liu et al. Macromol Biosci. 2012 Mar.

Abstract

Biodistribution, pharmacokinetics, and efficacy of prostate-cancer-targeted HPMA copolymer/DTX conjugates are evaluated in nude mice bearing prostate cancer C4-2 xenografts. PSMA-specific monoclonal antibodies 3F/11 are used as the targeting moiety. Control conjugates tumor accumulation to total background organs (heart, lung, kidney, liver, spleen and blood) accumulation increase substantially with time for the targeted conjugate, and the ratio at 48 h is 7-fold higher than that at 6 h. Preliminary evaluation of the efficacy of the conjugates in vivo show tumor growth inhibition for all HPMA copolymer/DTX conjugates.

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Figures

Figure 1
Figure 1
Synthesis scheme.
Figure 2
Figure 2
Characteristics of the conjugates. A: SEC profiles measured on the AKTA system, Superose 6 HR10/30 column, buffer PBS (pH =6.5) + 30% acetonitrile. B: An example of DTX release by enzymatic hydrolysis with an excess of papain: enzyme 80 ×10−6 M; polymer (P-DTX) 2.01 mg ·mL−1; pH =6.0; GSH 2 ×10−3 M; EDTA 2 ×10−3 M. C: Cleavage by cathepsin B: enzyme 8 ×10−6 M, polymer 2 mg ·mL−1, buffer as for B. D: DTX hydrolysis by human plasma and in buffer different pH.
Figure 3
Figure 3
Binding of targeted and non-targeted HPMA copolymer/ DTX conjugates. Saturated binding was performed using C4-2 cells. A: Free antibody; B: P-3F/11; and C: P-DTX-3F/11. Results are expressed as means of triplicate ± SD. Some of SDs are too small to be visible.
Figure 4
Figure 4
Biodistribution of targeted and non-targeted HPMA copolymer/DTX conjugates after intravenous administration to nude mice bearing C4-2 xenografts. P-DTX-3F/11 and P-DTX-IgG were administered at 20 μg protein (3F/11 or IgG) and 21 μg HPMA copolymer for each mouse with 0.1 μCi 125I-labeled conjugates as a tracer. P-DTX was administered with 0.1 μCi125I-labeled conjugates and 21 μg HPMA copolymer per mouse. Activity per organ is expressed as % injected dose per gram of tissue (% ID ·g−1). Necropsy was performed at indicated time intervals post injection. Results are displayed as mean ±SD (n =3).
Figure 5
Figure 5
Blood clearance of 125I-labeled HPMA copolymer/DTX-immunoglobulin conjugates. Squares: P-DTX-IgG; diamonds: P-DTX-3F/11; triangles: P-DTX. Results are expressed as mean ±SD (n =3).
Figure 6
Figure 6
Growth inhibition of subcutaneous prostate cancer C4-2 xenografts in nude mice. Treatment was started when the tumor reached a size of ≈100 mm2 (day 0). The mice (n =3) received intravenous injections of 2 mg ·kg−1 DTX equivalent on days 0, 3, 6, 9, and 13. Values are the means ±SD. Squares: untreated control; diamonds: P-DTX; Triangles: P-DTX-IgG; circles: P-DTX-3F/11.
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