The main purpose of this study was to develop a prostate-specific membrane antigen (PSMA) antibody-conjugated drug-loaded nanomicelles using MPEG--PLA-PCL-PLA-PEG-NH2 pentablock copolymer for targeted delivery of hydrophobic anticancer drugs to prostate cancer cells. During this experiment, monomers of L-lactide, ε-caprolactone, poly(ethylene glycol)-methyl ether, and poly(ethylene glycol)-NH2 were used to prepare pentablock copolymer using the ring opening technique. The pentablock nanomicellar (PBNM) formulation was prepared by the evaporation-rehydration method. The resultant pentablock nanomicelles were then conjugated with PSMA antibody resulting in PSMA-Ab-PTX-PBNM. Both the block copolymers and the nanomicelles were analyzed by hydrogen nuclear magnetic resonance (H-NMR), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The obtained nanomicelles (NM) were then analyzed for size and zeta potential using dynamic light scattering-dynamic laser scattering (DLS) and then further submitted to H-NMR and TEM analyses. The XRD, FTIR, and the H-NMR analyses confirmed the structure of the pentablock copolymers. The average size for conjugated nanomicellar was 45 nm ± 2.5 nm. The average (ζ-potential) was around − 28 mV. H-NMR and FTIR analysis done on PSMA-coupled paclitaxel-loaded PBNM showed peaks characteristic of the drug (paclitaxel) and the polymer, confirming the successful encapsulation. TEM analysis showed well-defined spherical morphology and confirmed the size range obtained by the DLS. In vitro release studies revealed sustained slow of PTX in phosphate buffer solution (PBS). Confocal scanning microscopy (TEM) of coumarin6-loaded in PBNM indicated that pentablock nanomicelles were internalized into the prostate cancer (PC-3) cells. Cell proliferation assay showed that nanomicelles ferried paclitaxel into the PC-3 cells and subsequently reduced the cell proliferation. The results depict PTX-PBNM-Ab as a suitable carrier for targeted delivery of drugs to prostate cancer cells.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Patel SP, Vaishya R, Pal D, Mitra AK. Novel pentablock copolymer-based nanoparticulate systems for sustained protein delivery. AAPS PharmSciTech. 2015;16(2):327–43.
Vaishya RD, Gokulgandhi M, Patel S, Minocha M, Mitra AK. Novel dexamethasone-loaded nanomicelles for the intermediate and posterior segment uveitis. AAPS PharmSciTech. 2014;15(5):1238–51.
Tamboli V, Mishra GP, Mitra AK. Novel pentablock copolymer (PLA-PCL-PEG-PCL-PLA) based nanoparticles for controlled drug delivery: effect of copolymer compositions on the crystallinity of copolymers and in vitro drug release profile from nanoparticles. Colloid Polym Sci. 2013;291(5):1235–45.
Youm I, Agrahari V, Murowchick JB, Youan BB. Uptake and cytotoxicity of docetaxel-loaded hyaluronic acid-grafted oily core nanocapsules in MDA-MB 231 cancer cells. Pharm Res. 2014;31(9):2439–52.
Wei Z, Hao J, Yuan S, Li Y, Juan W, Sha X, et al. Paclitaxel-loaded Pluronic P123/F127 mixed polymeric micelles: formulation, optimization and in vitro characterization. Int J Pharm. 2009;376(1–2):176–85.
Xia D, Lai DV, Wu W, Webb ZD, Yang Q, Zhao L, et al. Transition from androgenic to neurosteroidal action of 5alpha-androstane-3alpha, 17beta-diol through the type A gamma-aminobutyric acid receptor in prostate cancer progression. J Steroid Biochem Mol Biol 2017.
Vadlapudi AD, Cholkar K, Vadlapatla RK, Mitra AK. Aqueous nanomicellar formulation for topical delivery of biotinylated lipid prodrug of acyclovir: formulation development and ocular biocompatibility. J Ocul Pharmacol Ther. 2014;30(1):49–58.
Chen Y, Su N, Zhang K, Zhu S, Zhao L, Fang F, et al. In-depth analysis of the structure and properties of two varieties of natural luffa sponge fibers. Materials. 2017;10(5).
Reddy KO, Maheswari CU, Dhlamini MS, Mothudi BM, Kommula VP, Zhang J, et al. Extraction and characterization of cellulose single fibers from native african napier grass. Carbohydr Polym. 2018;188:85–91.
Ogieglo W, Tempelman K, Napolitano S, Benes NE. Evidence of a transition layer between the free surface and the bulk. J Phys Chem lett. 2018;9(6):1195–9.
Jia C, Li Y, Zhang S, Fei T, Pang S. Thermogravimetric analysis, kinetic study, and pyrolysis-GC/MS analysis of 1,1′-azobis-1,2,3-triazole and 4,4′-azobis-1,2,4-triazole. Chem Central J. 2018;12(1):22.
Patel SP, Vaishya R, Yang X, Pal D, Mitra AK. Novel thermosensitive pentablock copolymers for sustained delivery of proteins in the treatment of posterior segment diseases. Protein Pept lett. 2014;21(11):1185–200.
Patel SP, Vaishya R, Patel A, Agrahari V, Pal D, Mitra AK. Optimization of novel pentablock copolymer based composite formulation for sustained delivery of peptide/protein in the treatment of ocular diseases. J Microencapsul. 2016;33(2):103–13.
Agrahari V, Li G, Agrahari V, Navarro I, Perkumas K, Mandal A, et al. Pentablock copolymer dexamethasone nanoformulations elevate MYOC: in vitro liberation, activity and safety in human trabecular meshwork cells. Nanomedicine. 2017;12(16):1911–26.
Agrahari V, Agrahari V, Mitra AK. Nanocarrier fabrication and macromolecule drug delivery: challenges and opportunities. Ther Deliv. 2016;7(4):257–78.
Sawdon AJ, Peng CA. Polymeric micelles for acyclovir drug delivery. Colloids Surf B Biointerfaces. 2014;122:738–45.
Lian H, He Z, Meng Z. Rational design of hybrid nanomicelles integrating mucosal penetration and P-glycoprotein inhibition for efficient oral delivery of paclitaxel. Colloids Surf B Biointerfaces. 2017;155:429–39.
Youm I, Youan BB. Uptake mechanism of furosemide-loaded pegylated nanoparticles by cochlear cell lines. Hear Res. 2013;304:7–19.
Jones LJ, Gray M, Yue ST, Haugland RP, Singer VL. Sensitive determination of cell number using the CyQUANT (R) cell proliferation assay. J Immunol Methods. 2001;254(1–2):85–98.
Ihms EC, Brinkman DW. Thermogravimetric analysis as a polymer identification technique in forensic applications. J Forensic Sci. 2004;49(3):505–10.
Hoque ME, Hutmacher DW, Feng W, Li S, Huang MH, Vert M, et al. Fabrication using a rapid prototyping system and in vitro characterization of PEG-PCL-PLA scaffolds for tissue engineering. J Biomater Sci Polym ed. 2005;16(12):1595–610.
Cholkar K, Gunda S, Earla R, Pal D, Mitra AK. Nanomicellar topical aqueous drop formulation of rapamycin for back-of-the-eye delivery. AAPS PharmSciTech. 2015;16(3):610–22.
Kasten BB, Liu T, Nedrow-Byers JR, Benny PD, Berkman CE. Targeting prostate cancer cells with PSMA inhibitor-guided gold nanoparticles. Bioorg Med Chem Lett. 2013;23(2):565–8.
Murphy GP, Snow P, Simmons SJ, Tjoa BA, Rogers MK, Brandt J, et al. Use of artificial neural networks in evaluating prognostic factors determining the response to dendritic cells pulsed with PSMA peptides in prostate cancer patients. Prostate. 2000;42(1):67–72.
Zuccolotto G, Fracasso G, Merlo A, Montagner IM, Rondina M, Bobisse S, et al. PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models. PLoS One. 2014;9(10):e109427.
Jin J, Sui B, Gou J, Liu J, Tang X, Xu H, et al. PSMA ligand conjugated PCL-PEG polymeric micelles targeted to prostate cancer cells. PLoS One. 2014;9(11):e112200.
Patil Y, Shmeeda H, Amitay Y, Ohana P, Kumar S, Gabizon A. Targeting of folate-conjugated liposomes with co-entrapped drugs to prostate cancer cells via prostate-specific membrane antigen (PSMA). Nanomedicine. 2018;14:1407–16.
Zhao Y, Duan S, Zeng X, Liu C, Davies NM, Li B, et al. Prodrug strategy for PSMA-targeted delivery of TGX-221 to prostate cancer cells. Mol Pharm. 2012;9(6):1705–16.
Pearce AK, Simpson JD, Fletcher NL, Houston ZH, Fuchs AV, Russell PJ, et al. Localised delivery of doxorubicin to prostate cancer cells through a PSMA-targeted hyperbranched polymer theranostic. Biomaterials. 2017;141:330–9.
Ben Jemaa A, Sallami S, Ceraline J, Oueslati R. A novel regulation of PSMA and PSA expression by Q640X AR in 22Rv1 and LNCaP prostate cancer cells. Cell Biol Int. 2013;37(5):464–70.
Wolf P, Gierschner D, Buhler P, Wetterauer U, Elsasser-Beile U. A recombinant PSMA-specific single-chain immunotoxin has potent and selective toxicity against prostate cancer cells. Cancer Immunol Immunother. 2006;55(11):1367–73.
Salgaller ML, Lodge PA, McLean JG, Tjoa BA, Loftus DJ, Ragde H, et al. Report of immune monitoring of prostate cancer patients undergoing T-cell therapy using dendritic cells pulsed with HLA-A2-specific peptides from prostate-specific membrane antigen (PSMA). Prostate. 1998;35(2):144–51.
Feldmann A, Arndt C, Bergmann R, Loff S, Cartellieri M, Bachmann D, et al. Retargeting of T lymphocytes to PSCA- or PSMA positive prostate cancer cells using the novel modular chimeric antigen receptor platform technology “UniCAR”. Oncotarget. 2017;8(19):31368–85.
Yoo HS, Park TG. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer. J Control Release. 2001;70(1–2):63–70.
The authors would like to express the most sincere gratitude to: (1) CAPES Foundation, Ministry of Education of Brazil, Brasília - DF 70040-020, Brazil, for funding through SwB scholarship; (2) Ms. Barbara Fegley of the University of Kansas Medical Center for TEM facility; and (3) Mrs. Abrar Alnafisah for the FTIR facility.
Guest Editors: Mahavir Bhupal Chougule, Vijaykumar B. Sutariya and Sudip K. Das
About this article
Cite this article
Owiti, A.O., Pal, D. & Mitra, A. PSMA Antibody-Conjugated Pentablock Copolymer Nanomicellar Formulation for Targeted Delivery to Prostate Cancer. AAPS PharmSciTech 19, 3534–3549 (2018). https://doi.org/10.1208/s12249-018-1126-9
- PSMA antibody
- prostate cancer
- pentablock copolymer nanomicelles
- targeted delivery