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

Lv, Qingzhi; Yang, Jincheng; Zhang, Ruoshi; Yang, Zhiman; Yang, Zhengtao; Wang, Yongjun; Xu, Youjun; Zhang, He

doi:10.1021/acs.molpharmaceut.8b00026

Cited by 33 publications

(27 citation statements)

References 25 publications

(63 reference statements)

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“…These profiles clearly show that Taxol release from KPs is a pH-dependent drug release profile. Most of the time, drug release profiles display a biphasic release trend, including an initial burst during the first few hours followed by a more sustained release in the following entire study duration [ 39 , 40 ]. There was no initial burst type of release in our drug delivery system.…”

Section: Resultsmentioning

confidence: 99%

Noyes-Whitney Dissolution Model-Based pH-Sensitive Slow Release of Paclitaxel (Taxol) from Human Hair-Derived Keratin Microparticle Carriers

Wimalasiri

Dunuweera

et al. 2021

BioMed Research International

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This paper describes a convenient and straightforward method developed to extract keratin particles (KPs) from human hair. It also involves their characterization by several methods and encapsulation of the anticancer drug Paclitaxel (Taxol) within them, aiming for targeted delivery to cancerous sites and slow release at their vicinity. The KPs obtained were in micrometer in size. They are capable of encapsulating Taxol within them with a high encapsulation efficiency of 56% and a drug loading capacity of 2.360 g of Taxol per g keratin. As revealed by the SEM elemental analysis, KPs do not contain any toxic metal ion, and hence, they pose no toxicity to human cells. The pH-dependent release kinetics of the drug from KPs indicates that the drug is released faster when the pH of the solution is increased in the 5.0 to 7.0 pH range. The release kinetics obtained is impressive, and once targeted to the cancerous sites, using cancer directing agents, such as folic acid; a glutamate urea ligand known as DUPA; aminopeptidase N, also known as CD13; and FAP-α-targeting agents, the slow release of the drug is expected to destroy only the cancerous cells. The Noyes-Whitney dissolution model was used to analyze the release behavior of Taxol from KPs, which shows excellent fitting with experimental data. The pH dependence of drug release from keratin is also explained using the 3-D structures and keratin stability at different pH values.

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Section: Resultsmentioning

confidence: 99%

Noyes-Whitney Dissolution Model-Based pH-Sensitive Slow Release of Paclitaxel (Taxol) from Human Hair-Derived Keratin Microparticle Carriers

Wimalasiri

Dunuweera

et al. 2021

BioMed Research International

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“…In conclusion, information on the internalization and reduction of disulfide bonds can be critical to the design of ligand-targeted drugs, especially in cases where targeting ligand and drug are connected by a disulfide bond [23,24] . However, while PSMA is a commonly used receptor for such ligand-targeted therapeutic agents [14][15][16][17][18][19]25] , and recycling of the PSMA receptor has been studied [26] , the kinetics of disulfide bond cleavage in PSMA-containing intracellular compartments has not been thoroughly explored. Therefore, in order to measure these kinetics and gain a greater understanding of the reducing environment within PSMA-trafficking endosomes, a PSMA-targeted FRET-based probe containing the DUPA-targeting ligand linked to a disulfide-bridged FRET donor/acceptor pair was synthesized.…”

Section: Discussionmentioning

confidence: 99%

“…As numerous prostate specific membrane antigen (PSMA)-targeted drugs and imaging agents have been studied in both animals [14][15][16] and humans bearing prostate cancers [17][18][19] , we elected to explore this question using a similar fluorescent FRET pair targeted to prostate cancer cells with a PSMA-targeting ligand. In this brief communication, we show that the PSMA-targeted conjugate is internalized quickly and then traffics in approximately equal amounts through an intracellular compartment in which the disulfide bond is rapidly reduced, i.e., similar to folate-targeted conjugates, or an endosome in which no disulfide reduction occurs.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the reducing potential of PSMA-containing endosomes by FRET imaging

Chelvam¹,

Shen²,

Putt³

2020

CDR

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Aim: Ligand-targeted therapeutics are experiencing increasing use for treatment of human diseases due to their ability to concentrate a desired drug at a pathologic site while reducing accumulation in healthy tissues. For many ligand-targeted drug conjugates, a critical aspect of conjugate design lies in engineering release of the therapeutic payload to occur only after its internalization by targeted cells. Because disulfide bond reduction is frequently exploited to ensure intracellular drug release, an understanding of the redox properties of endocytic compartments can be critical to ligand-targeted drug design. While the redox properties of folate receptor trafficking endosomes have been previously reported, little is known about the trafficking of prostate-specific membrane antigen (PSMA), a receptor that is experiencing increasing use for drug targeting in humans. Methods: To obtain this information, we have constructed a PSMA-targeted fluorescence resonance energy transfer pair that reports on disulfide bond reduction by changing fluorescence from red to green. Results: We show here that this reporter exhibits rapid and selective uptake by PSMA-positive cells, and that reduction of its disulfide bond proceeds steadily but incompletely following internalization. The fact that maximal disulfide reduction reaches only ~50%, even after 24 h incubation, suggests that roughly half of the conjugates must traffic through endosomes that display no reducing capacity. folate trafficked conjugates, it also follows that not all internalizing receptors are translocated through similar intracellular compartments. Taken together, these data suggest that the efficiency of disulfide bond reduction must be independently analyzed for each receptor trafficking pathway when disulfide bond reduction is exploited for intracellular drug release.

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“…It contains a binuclear zinc site and is active as a glutamate carboxypeptidase, catalyzing the hydrolytic cleavage of α- or γ-linked glutamates from peptides or small molecules [ 17 , 18 , 19 , 20 ]. Based on the above, PSMA is becoming one of the current research hotspots and is an excellent target for the anti-angiogenesis targeted therapy [ 19 , 20 , 21 , 22 , 23 ]. The enzymatic activity of PSMA can be exploited for the design of prodrugs, in which an inactive form of the cytotoxic drug is selectively cleaved and thereby activated only at cells that express PSMA within the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

PSMA-Oriented Target Delivery of Novel Anticancer Prodrugs: Design, Synthesis, and Biological Evaluations of Oligopeptide-Camptothecin Conjugates

Zhou

Yan

et al. 2018

IJMS

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Clinical applications of camptothecin (CPT) have been heavily hindered due to its non-targeted toxicity, active lactone ring instability, and poor water solubility. Targeted drug delivery systems may offer the possibility to overcome the above issues as reported. In this research, a series of prostate-specific membrane antigen (PSMA)-activated CPT prodrugs were designed and synthesized by coupling water-soluble pentapeptide, a PSMA hydrolyzing substrate, to CPT through an appropriate linker. The cytotoxicity of CPT prodrugs was masked temporarily until they were hydrolyzed by the PSMA present within the tumor sites, which restored cytotoxicity. The in vitro selective cytotoxic activities of the prodrugs were evaluated against PSMA-expressing human prostate cancer cells LNCaP-FGC and non-PSMA-expressing cancer cells HepG2, Hela, MCF-7, DU145, PC-3 and normal cells MDCK, LO2 by standard methylthiazol tetrazolium (MTT) assay. Most of the newly synthesized CPT prodrugs showed excellent selective toxicity to PSMA-producing prostate cancer cells LNCaP-FGC with improved water solubility. From among the library, CPT-HT-J-ZL12 showed the best cytotoxic selectivity between the PSMA-expressing and the non-PSMA-expressing cancer cells. For example, the cytotoxicity of CPT-HT-J-ZL12 (IC50 = 1.00 ± 0.20 µM) against LNCaP-FGC (PSMA+) was 40-fold, 40-fold, 21-fold, 5-fold and 40-fold, respectively, higher than that against the non-PSMA-expressing cells HepG2 (IC50 > 40.00 µM), Hela (IC50 > 40.00 µM), MCF-7 (IC50 = 21.68 ± 4.96 µM), DU145 (IC50 = 5.40 ± 1.22 µM), PC-3 (IC50 = 42.96 ± 3.69 µM) cells. Moreover, CPT-HT-J-ZL12 exhibited low cytotoxicity (IC50 > 40 μM) towards MDCK and LO2 cells. The cellular uptake experiment demonstrated the superior PSMA-targeting ability of the CPT-HT-J-ZL12, which was significantly accumulated in LNCaP-FGC (PSMA+), while it was minimized in HepG2 (PSMA−) cells. Further cell apoptosis analyses indicated that it showed a dramatically higher apoptosis-inducing activity in LNCaP-FGC (PSMA+) cells than in HepG2 (PSMA−) cells. Cell cycle analysis indicated that CPT-HT-J-ZL12 could induce cell cycle arrest at the S phase.

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

Cited by 33 publications

References 25 publications

Noyes-Whitney Dissolution Model-Based pH-Sensitive Slow Release of Paclitaxel (Taxol) from Human Hair-Derived Keratin Microparticle Carriers

Noyes-Whitney Dissolution Model-Based pH-Sensitive Slow Release of Paclitaxel (Taxol) from Human Hair-Derived Keratin Microparticle Carriers

Evaluation of the reducing potential of PSMA-containing endosomes by FRET imaging

PSMA-Oriented Target Delivery of Novel Anticancer Prodrugs: Design, Synthesis, and Biological Evaluations of Oligopeptide-Camptothecin Conjugates

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