Surface Modification of Liposomes by a Lipopolymer Targeting Prostate Specific Membrane Antigen for Theranostic Delivery in Prostate Cancer

Abstract

Prostate specific membrane antigen (PSMA) is a marker for diagnosis and targeted delivery of therapeutics to advanced/metastasized prostate cancer. We report a liposome-based system for theranostic delivery to PSMA-expressing (PSMA+) LNCaP cells. A lipopolymer (P3) comprising of PSMA ligand (PSMAL), polyethylene glycol (PEG2000), and palmitate was synthesized and post-inserted into the surface of preformed liposomes. These P3-liposomes were loaded with doxorubicin and radiolabeled with 99mTc radionuclide to study their theranostic characteristics. Differential expression of PSMA on LNCaP and PC3 cells was confirmed by immunoblotting as well as by uptake of PSMAL labeled with 18F radionuclide. We found that the uptake of 99mTc-labeled P3-liposomes by LNCaP cells was >3-fold higher than 99mTc-labeled Plain-liposomes; the amount of doxorubicin delivered to LNCaP cells was also found to be >3-fold higher by P3-liposomes. Cell-based cytotoxicity assay results showed that doxorubicin-loaded P3-liposomes were significantly more toxic to LNCaP cells (p < 0.05), but not to PSMA-negative PC3 cells. Compared to doxorubicin-loaded Plain-liposomes, the IC50 value of doxorubicin-loaded P3-liposomes was reduced by ~5-fold in LNCaP cells. Together, these results suggest that surface functionalization of liposomes with small PSMA-binding motifs, such as PSMAL, can provide a viable platform for specific delivery of theranostics to PSMA+ prostate cancer.

Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance

“…With regard to cancer therapy, liposomes provide a good platform for in vivo delivery of many anti-tumor drugs, such as doxorubicin and paclitaxel, among other chemotherapeutic agents, as well as nucleic acids ( Chen et al, 2010 ; Wang X. et al, 2017 ). In the field of breast and prostate cancer ( Yari et al, 2019 ), the application of liposomes has been increasingly common ( Satsangi et al, 2015 ; Tang B. et al, 2020 ). Multiple paclitaxel liposomes have been demonstrated to have higher anti-tumor efficiency and improved bioavailability compared to free paclitaxel ( Han et al, 2020 ).…”

Self-Assembly of Organic Nanomaterials and Biomaterials: The Bottom-Up Approach for Functional Nanostructures Formation and Advanced Applications

“…For these reasons, lipid nanostructures are considered a versatile nano-platform in the field of nanomedicine and biotechnology [153,154]. Recently, a P3 lipopolymer (comprising of prostate-specific membrane antigen (PSMA) ligand, polyethylene glycol (PEG2000), and palmitate) was employed for the functionalization of liposomes for the targeted delivery of drugs and diagnostics to PSMA+ advanced/metastatic prostate tumors [155]. The investigation showed that doxorubicin loaded functionalized liposomes evidenced a higher toxicity to human prostate cancer LNCaP cells lines with respect to the non-targeted liposomes.…”

Anchoring Property of a Novel Hydrophilic Lipopolymer, HDAS-SHP, Post-Inserted in Preformed Liposomes

“…Realizing these problems, Uster et al introduced the concept of post-insertion, as a technique where preformed liposomes were modified only at their external surface [36]. This technique has been successfully reported for many liposome-based drug and biologic delivery systems, and has now become central to liposome development in our lab [24,34,35,37,38]. In post-insertion technique, it is important to present stealth lipopolymers to the preformed liposomes in monomeric form.…”

“…The CMC of lipopolymers, namely HDAS-SHP, HDAS-PEG 2000 , and DSPE-PEG 2000 , was determined by PC1 photon-counting spectrofluorimeter analyses (ISS, Champaign, IL, USA), as described elsewhere [17,24]. Hydro-alcoholic solution (10% v/v ethanol in phosphate-buffered saline) of N -phenyl-1-naphthylamine (NPN, 1 µM) was used as a fluorescent probe.…”