Table 2.

List of PSMA based therapeutics developed with focus on Chemotherapy and Gene therapy

Therapeutic payload	Delivery vector	Targeting ligand	In vitro model	In vivo model	Concluding remarks	References
Chemotherapy
Methotrexate	PAMAM dendrimer	Glutamate urea	LnCap, PC3 cells	N/A	Nanoparticle binding and uptake observed in LnCap cells (PSMA+) and not in PC3 cells (PSMA‐).	(Huang et al., 2014)
CpG and Doxorubicin	Dendrimer	DNA‐A9 PSMA (RNA aptamer hybrid)	RAW264.7, LNCaP, 22RV1, DU145, and PC3 cells	BALB/c mice (22RV1 xenograft tumour model)	Seventy‐eight per cent decrease in tumour volume observed in animals treated with targeted nanoparticles compared with controls.	(Lee et al., 2011)
Mono methylauristatin E	N/A	PSMA Monoclonal antibody	LNCaP, C4–2, CWR22rv1, and PC3, DU145, MDA PCa2b cells	Athymic nude mice (C4–2 xenograft tumour model)	1000‐fold better cell death observed in cells that expressed PSMA.	(Wang et al., 2011)
					Effective in treating tumours in a C4–2 xenograft model that had progressed following treatment with docetaxel.
Mono methylauristatin E	N/A	PSMA monoclonal antibody	LuCap 96CR PDM model	SCID mice	Complete tumour regression in LuCaP 96 CR xenograft mouse model, when treated with drug‐antibody conjugate.	(DiPippo et al., 2015)
					The PDX model displayed a high level of PSMA expression.
Docetaxel	PLA–PEG/PLGA‐PEG	ACUPA (small molecule)	N/A	Athymic nude mice (LnCap xenograft model) / Male Sprague–Dawley rats / Cynomolgus monkeys	Targeted nanoparticles had increased tumour accumulation and suppressed tumour growth in tumour bearing mice.	(Hrkach et al., 2012)
Epirubicin	PEG	RNA aptamer (A10)	PC3 and LnCap cells	N/A	Reduced toxicity observed in PSMA‐ cell line when treated with PEG‐Apt‐Epi formulation versus Epirubicin alone.	(Taghdisi et al., 2013)
					No difference in cell viability observed in PSMA+ cell line, when treated with epirubicin alone or PEG‐Apt‐Epi
Doxorubicin	PLA–PEG micelles	RNA aptamer (A10)	CWR22Rν1 cells	Athymic nude mice (CWR22Rν1 cells xenograft model)	Doxorubicin‐loaded micelles showed increased uptake in PSMA+ 22Rv1 cells via PSMA‐mediated endocytosis.	(Xu et al., 2013)
Doxorubicin	Liposome	RNA aptamer	LnCap and PC3 cells	BALB/c athymic nude mice (LnCap xenograft model)	Targeted liposomes containing docetaxel were significantly more toxic to PSMA + cell line (LNCaP) than compared with PC‐3 cell line (PSMA ‐) and also showed significant tumour regression in comparison untargeted liposomes or drug alone.	(Baek et al., 2014)
Circumin	PLGA/PLL/PVA	PSMA antibody	LnCap, DU145, PC3 and C4–2 cells	Athymic nude mice	PSMA antibody tagged PLGA curcumin nanoparticles showed specific targeting in C4–2 cells (PSMA +) in a xenograft mouse model	(Yallapu et al., 2014)
Indenoisoquinoline topoisomerase I inhibitor	N/A	DUPA	22RV1 cells	Athymic nude mice (22RV1 cells xenograft model)	After 40 days, complete regression of tumour growth was observed in the animals treated with DUPA‐drug conjugate.	(Roy et al., 2015)
					DUPA conjugate exibited PSMA receptor‐mediated uptake.
Toremifene	PLGA‐PEG nanoparticles	PSMA antibody	PC3M cells	Athymic nude mice	Incorporation of oestrogen receptor‐α (ERα) blocker, toremifene, into PLGA nanoparticle resulted in a 15‐fold increase in its uptake when compared with free toremifene.	(Hariri et al., 2015)
					The model used was modified PC‐3 cells to express PSMA (PC3M) orthotopically implanted into mouse prostate.
Doxorubicin	PEGylated PLA nanoparticle	RNA aptamer (A10)	LNCaP and PC‐3 cells and canine prostatic adenocarcinoma cell line (cHSA) cell line	BALB/c mice	Mice treated with aptamer‐conjugate showed a twofold increase in the amount of necrotic tissue in the tumour compared with the non‐targeted nanoparticles.	(Tang et al., 2015)
					A significant reduction in tumour burden in the aptamer group after 7 days (~70%) was observed, when compared with the non‐targeted group (14% reduction).
Docetaxel	HPMA co polymer	DUPA	C4–2 and PC3 cell line	Athymic nude mice (C4–2 xenograft model)	Lower IC50 of targeted nanoparticles with DTX (3.18 ± 0.42 nM) compared with untargeted counterparts (4.14 ± 1.03 nM).	(Peng et al., 2013)
					Significantly (p < 0.05) reduction in tumour volume with targeted nanoparticles vs. untargeted nanoparticles (<800 mm3 vs. >1500 mm3 at 42 days post injection, respectively).
Thapsigargin	Drug conjugated with peptide (Asp‐Glu‐Glu‐Glu‐Glu‐Glu)	N/A	LNCaP, MDA‐PCa2b, TSU, SN12C, and MCF‐7 cells, CWR22R‐H xenograft	Nude mice (Harlan Sprague Dawley)	This delivery vector takes advantage of the glutamate carboxypeptidase activity of PSMA to cleave the glutamate residues from the peptide to form 8‐O‐(12‐aminododecanoyl)‐8‐O‐debutanoyl thapsigargin (12ADT)‐βAsp.	(Denmeade et al., 2012)
					This prodrug is over 60‐fold more toxic to PMSA + cells than PSMA – cells.
					Delivery of thapsigargin in the prodrug form is 150‐fold more effective than free thapsigargin.
					Tumour regression and growth inhibition was observed in six in vivo tumour xenograft models with the prodrug.
Suicide enzyme yCD	N/A	N/A	LnCap and PC3 cells	N/A	Significant reduction of cell viability in PSMA+ cell lines (~ 60% reduction), in comparison to PSMA‐ cell line (PC3)	(Martin et al., 2014)
RNA aptamer A9 g	N/A	RNA apatmer A9 g	CT26, PC3 (PSMA +/−) and 22Rv1	SCID mice	A9 g binds and inhibits the enzymatic activity of PSMA.	(Dassie et al., 2014)
					*A9 g demonstrated the ability to reduce cell invasion (~ 75% reduction) and migration (~ 70% reduction) of prostate cancer cells engineered to express PSMA (PC‐3)
P13k Inhibitor ZSTK474 and immunotoxin J591PE	N/A	N/A	LnCap, C4–2 and BT‐549	BALB/c nude mice	The combination of the 2 drugs resulted in increased apoptosis and cell deaths in PSMA+ cell lines (LNCaP and C4–2) compared with PSMA‐ (BT549).	(Baiz et al., 2013)
TGX‐221	PEG‐PCL micelles	RNA aptamer A10	PC3, DU145 and LnCap cells	BALB/c nude mice	TGX‐221 is a selective inhibitor of the P13K p110β catalytic subunit.	(Zhao et al., 2012)
					Micelles that were targeted to PSMA resulted in a significant increase in uptake of drug in PSMA+ cells.
TGX‐221	PEG‐PCL micelles	–	LAPC‐4, LNCaP, C4–2 and 22RV1 cells	Nude mice (LAPC‐4, LNCaP, C4–2 and 22RV1 cells used for xenograft models)	*Complete inhibition of tumour growth in four mouse xenograft models (LAPC‐4, LNCaP, C4–2 and 22RV1).	(Chen et al., 2015)
					Induction of apoptosis and reduction of PSA levels by approximately 80% in the four models tested.
Cisplatin	PLGA‐b‐PEG NPs	RNA apatmer	LnCap cells	Sprague Dawley rats and Swiss Albino mice, BALB/c mice	Achieved greater maximum tolerated dose (MTD) for cisplatin was greater when encapsulated in NP than for free cisplatin.	(Dhar et al., 2011)
					Enhanced residence time in blood.
					Reduction in tumour growth at much lower platinum dose than than cisplatin.
Epigallocatechin 3‐gallate (EGCG)	PLGA‐PEG	DCL	LnCap cells and HUVEC cells	N/A	Significantly greater reductions in LNCaP cell viability when EGCG was complexed in targeted vs non‐targeted NP.	(Sanna et al., 2011)
Genetherapy
siRNA targeting Notch1	Two fusion proteins and a truncated protamine	PSMA antibody	LnCap adn DU145 cells	BALB/c nude mice	Significant KD of Notch1 in LNCaP mouse xenograft model	(Su et al., 2013)
siRNA targeting choline kinase (ChK)	PLL‐PEG‐PEI	PSMA inhibitor	PC3 cells	SCID and BALB/c mice	Theranostic vector contains I111 for imaging, bacterial cytosine deaminase and siRNA targeting Chk.	(Chen et al., 2012)
					Specific uptake of targeted nanoparticles into PSMA+ PC3‐PIP tumours was observed.
					Nanoparticles were well tolerated with no liver or kidney toxicity and no immune response.
siRNA targeting PSMA	Lentivirus	N/A	LnCap, DU145 and HEK 293 T‐cells	N/A	Suppressed growth, migration and invasion of PSMA+ LNCap and DU145 cell lines	(Guo et al., 2011)
siRNA targeting mTOR	Lentivirus	N/A	RWPE1, LNCap, C4–2b and HEK293 cells	SCID mice (C4–2b xenografts)	Tumour growth was significantly retarded in SCID mice treated with LV‐PSMA‐shmTOR.	(Du et al., 2013)
ShRNA targeting DNAPK	N/A	Aptamer A10–3	DU145, LnCap and PC3 cells	Athymic nude mice	25% reduction in DNAPK expression in human prostate tissue by immunostaining compared with control aptamers.	(Ni et al., 2011)
					60% cell death in LNCaP cells treated with aptamer‐targeted shRNA.
					Combination of A10–3‐DNAPK and radiation treatment (6 Gy) resulted in a significant and extended tumour response in LNCaP tumours but not PC‐3 tumours.
MiR‐15a and miR‐16‐1	PAMAM‐PEG	Aptamer A10–3.2	PC3 ad LnCap cells	N/A	Targeted nanoparticles showed sixfold higher transfection efficiency in LNCaP cells (in relation to untargeted NP).	(Wu et al., 2011)
					Targeted nanoparticles also showed a 5.47 fold lower IC50 compared with non‐targeted control in LNCaP cells in vitro.
HSV‐TK and connexin43 gene	PAMAM dendrimer	Folate	LnCap, PC3, NIH3T3, HepG2,	Nude mice	HSV‐TK and connexion43 gene expression was driven by PSMA promoter.	(Chen et al., 2013)
					Expression of these genes was confined to LNCaP cells (but absent from PC‐3 cells).
Bcl‐xL shRNA (in combination with docetaxel)	PEI‐PEG	Aptamer	LnCap cells	N/A	Three‐fold higher transfection efficiency in LnCap cells with targeted nanoparticles.	(Kim et al., 2010)
					LNCaP cell viability fell from 81% to 21% 48 h after treatment with NPs, with virtually no toxicity in PC‐3 cells observed.
					IC50 value for the NPs loaded with docetaxel + shRNA was 17‐fold lower than for the drug and shRNA/Lipofectamine.
PLK1 siRNA	Liposome	Folate	PC3 and 22Rv1	BALB/c nude mice	Dual targeted liposomes with folate (for PSMA targeting) and a cleavable peptide that reveals a cell penetrating peptide in the presence of PSA.	(Xiang et al., 2013)
					twofold greater KD of PLK1 mRNA by targeted NPs in 22Rv1 xenograft mouse model compared with the non‐targeted control.
MiR‐15a and miR‐16‐1	Atelocollagen	Aptamer 10–3.2	PC3 and LnCap cells	BALB/c nude mice	5.4 fold higher uptake efficiency with targeted formulation in LnCap cells	(Hao et al., 2016)
					miRNA complexed with targeted formulations four‐fold lower IC50 value compared with untargeted forulation
					In a human PCa bone metastasis model, mean survival time for mice treated with miRNA/ATE was 38 days, while those treated with miRNA/ATE‐APT had an average survival time of 57 days.