Prostate-Specific Membrane Antigen Targeted Therapy of Prostate Cancer Using a DUPA–Paclitaxel Conjugate

Prostate cancer (PCa) is the most prevalent cancer among men in the United States and remains the second-leading cause of cancer mortality in men. Paclitaxel (PTX) is the first line chemotherapy for PCa treatment, but its therapeutic efficacy is greatly restricted by the nonspecific distribution <i>in vivo</i>. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of most PCa cells, and its expression level increases with cancer aggressiveness, while being present at low levels in normal cells. The high expression level of PSMA in PCa cells offers an opportunity for target delivery of nonspecific cytotoxic drugs to PCa cells, thus improving therapeutic efficacy and reducing toxicity. PSMA has high affinity for DUPA, a glutamate urea ligand. Herein, a novel DUPA–PTX conjugate is developed using DUPA as the targeting ligand to deliver PTX specifically for treatment of PSMA expressing PCa. The targeting ligand DUPA enhances the transport capability and selectivity of PTX to tumor cells via PSMA mediated endocytosis. Besides, DUPA is conjugated with PTX via a disulfide bond, which facilitates the rapid and differential drug release in tumor cells. The DUPA–PTX conjugate exhibits potent cytotoxicity in PSMA expressing cell lines and induces a complete cessation of tumor growth with no obvious toxicity. Our findings give new insight into the PSMA-targeted delivery of chemotherapeutics and provide an opportunity for the development of novel active targeting drug delivery systems for PCa therapy

Yield and monetary value for different crops.

<p>Crop yield determined by grain weight for rice, wheat and broad bean, dry leaf weight for tobacco, fresh stem and tuber weight for sugarcane and potato. Crop values based on market prices of 2067.02 US$per ton for tobacco, 284.15 US$ per ton for maize, 23.89 US$per ton for sugarcane, 64.59 US$ per ton for potato, 296.98 US$per ton for wheat, 483.97 US$ per ton for broad bean. Crop yield and value were for individual species within intercropping. Yields of tobacco-maize, sugarcane-maize and wheat-broad bean patterns were additional production compared with monocrops. Yields of potato intercropped with maize and maize intercropped with potato, compared with equal areas of monocrops are shown in <b>(bold)</b>. Statistical analyses: each survey plot was considered to be an experimental unit, and analyses were based on actual mean plot yields. Statistical analyses were conducted by software SPSS 13.0. One-tailed t-tests were used to determine if the yield differed significantly (p≤0.05).</p

Severity of main diseases of the crops in monocropping and intercropping systems.

<p>T = Tobacco brown leaf spot (<i>Alternaria alternate</i> Keissler); M = Maize northern leaf blight (<i>Setosphaeria turcica</i> Leonard); S = Sugarcane eye spot (<i>Bipolaris sacchari</i> (Butl) Shoemaker); P = Potato late blight (<i>Phytophthora infestans</i> (Mont.) de Bary); W = Wheat Stripe Rust (<i>Puccinia striiformis</i> West); B = Broad bean <i>chocolate</i> spot (<i>Botrytis fabae</i> Sard). m = disease severity for crop species grown in monoculture control plots; i = disease severity for the same crop species grown in intercropping plots in the same fields. Error bars are one s. e. m; n = 3. Statistical analyses were conducted by software SPSS 13.0. All differences between pairs are significant at P≤0.05 based on one-tailed t-test.</p

Land equivalent ratios for crop yields produced by intercropping.

<p>Land equivalent ratios (LERs) were calculated as (yield ha⁻¹ of crop A in intercropping/yield ha⁻¹ of crop A in monoculture)+(yield ha⁻¹ of crop B in intercropping/yield ha⁻¹ of crop B in monoculture).</p