Abstract
High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO’s therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers.
Highlights
Cervical cancer is the second most common cancer in women worldwide and imposes a disproportionately high burden (>80%) on the developing world [1,2]
Previous studies of folate surface receptor expression on the two cervical cancer cell lines investigated found that HeLa (HPV+) cells positively expressed folate receptor (FR) while HT-3 (HPV-) cells only minimally expressed the receptor
Results clearly demonstrated that folic acid (FA) conjugation to liposomes, even to a polyethylene glycol (PEG) spacer of similar length as the surrounding PEG brush, was able to selectively target FR-positive cells. Their targeting efficiency increased considerably when FA was conjugated to a longer PEG spacer, making L3 the logical choice as a delivery vehicle for arsenic to FR rich HeLa and KB cells with human papilloma virus (HPV) infection
Summary
Cervical cancer is the second most common cancer in women worldwide and imposes a disproportionately high burden (>80%) on the developing world [1,2]. Since the 1990s, HPV infection has been established as the causal agent of cervical cancer with undisputed epidemiological studies, augmented by molecular technology [3,4]. Further studies have indicated that HPV infection might be responsible for a subset of anal, vulvar, vaginal, penile, upper respiratory-digestive tract, and head and neck cancers [5,6,7,8]. Targeting HPV infection has become a priority in managing HPV-associated cancers, and an anti-HPV agent that can be taken up by HPV-infected cells is ideally required to enhance treatment and minimise off-target toxicity to surrounding non-HPV-infected cells and tissues [9]. Along with others, have shown that ATO, as a therapeutic drug, downregulated HPV oncogene expression and had an inhibitory effect on HPV-infected HeLa cells [10,11]. ATO has been reported to interfere in other cellular events, for instance tubulin polymerisation, DNA repair, and cell cycle progression [16]
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