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Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity.

ABSTRACT: Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL or Lipodox) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol-dioleoyl phosphatidylethanolamine (PEG-DOPE) amphiphilic co-polymer. The resultant R8-PEG-PE conjugate was introduced into the lipid bilayer of liposomes at 2 mol% of total lipid amount via spontaneous micelle-transfer technique. The liposomal modification did not alter the particle size distribution, as measured by Particle Size Analyzer and transmission electron microscopy (TEM). However, surface-associated cationic peptide increased zeta potential of the modified liposomes. R8-functionalized liposomes (R8-Dox-L) markedly increased the intracellular and intratumoral delivery of doxorubicin as measured by flow cytometry and visualizing by confocal laser scanning microscopy (CLSM) compared to unmodified Doxorubicin-loaded PEGylated liposomes (Dox-L). R8-Dox-L delivered loaded Doxorubicin to the nucleus, being released from the endosomes at higher efficiency compared to unmodified liposomes, which had marked entrapment in the endosomes at tested time point of 1h. The significantly higher accumulation of loaded drug to its site of action for R8-Dox-L resulted in improved cytotoxic activity in vitro (cell viability of 58.5 ± 7% for R8-Dox-L compared to 90.6 ± 2% for Dox-L at Dox dose of 50 ?g/mL for 4h followed by 24h incubation) and enhanced suppression of tumor growth (348 ± 53 mm(3) for R8-Dox-L, compared to 504 ± 54 mm(3) for Dox-L treatment) in vivo compared to Dox-L. R8-modification has the potential for broadening the therapeutic window of pegylated liposomal doxorubicin treatment, which could lead to lower non-specific toxicity.

SUBMITTER: Biswas S

PROVIDER: S-EPMC4157068 | biostudies-other | 2013 Aug

REPOSITORIES: biostudies-other

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Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity.

Biswas Swati S Dodwadkar Namita S NS Deshpande Pranali P PP Parab Shruti S Torchilin Vladimir P VP

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 20130117 3

Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL or Lipodox) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol-dioleoyl phosphatidylethanolamine (PEG-DOPE) amphiphilic co-polymer. The resultant R8-PEG-PE conjugate was introduced into the lipid bilayer of liposomes at 2 mol% of total lipid amount via spontaneous micelle-transfer technique. The liposomal modification did not ...[more]

PMID: 23333899

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Project description:Ovarian cancer stands as a leading cause of cancer-related deaths among women globally. This malignancy has hindered successful treatment attempts due to its inherent resistance to chemotherapy agents. The utilization of cisplatin and doxorubicin-loaded liposomes emerges as a strategically advantageous approach in the realm of biomedical applications. This strategy holds promise for augmenting drug efficacy, mitigating toxicity, refining pharmacokinetics, and facilitating versatile drug delivery while accommodating combination therapies. In pursuit of scholarly investigations, the eminent databases, including PubMed/MEDLINE, ScienceDirect, Scopus, and Google Scholar, were meticulously scrutinized. Within this study, a nano-liposomal formulation was meticulously designed to serve as a co-delivery system. This system was optimized by varying lipid concentrations, hydration time, and DSPC: cholesterol molar ratios to efficiently encapsulate and load doxorubicin (DOX) and cisplatin (CIS) to overcome drug resistance problems. The Lipo (CIS + DOX) formulation underwent rigorous characterization including dimensions, entrapment efficiencies and drug release kinetics. Notably, the entrapment efficiency of cisplatin and doxorubicin loaded liposomal nanoparticles was an impressive 85.29 ± 1.45 % and 73.62 ± 1.70 %, respectively. Furthermore, Lipo (CIS + DOX) drug release kinetics exhibited pH-dependent properties, with lower drug release rates at physiological pH (7.4) than acidic (pH 5.4). Subsequent cytotoxicity assays revealed the enhanced biocompatibility of dual-drug liposomes with HFF cells compared to free drug combinations. Impressively, CIS and DOX-loaded liposomes induced significant cytotoxicity against A2780 in comparison to free drugs and combinatorial free drugs. Furthermore, the CIS and DOX-loaded liposome showed induced apoptotic potential and cell cycle arrest in A2780 compared to CIS, DOX, and their combination (CIS + DOX). Combining CIS and DOX via liposomal nanoparticles introduces a promising therapeutic avenue for addressing ovarian cancer. These nano-scale carriers hold the potential for attenuating the untoward effects of singular drugs and their attendant toxicities.

Project description:BackgroundColorectal cancer is one of the prominent leading causes of fatality worldwide. Despite recent advancements within the field of cancer therapy, the cure rates and long-term survivals of patients suffering from colorectal cancer have changed little. The application of conventional chemotherapeutic agents like doxorubicin is limited by some drawbacks such as cardiotoxicity and hematotoxicity. Therefore, nanotechnology has been exploited as a promising solution to address these problems. In this study, we synthesized and compared the anticancer efficacy of doxorubicin-loaded liposomes that were surface engineered with the 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-matrix metalloproteinase-2 (MMP-2) cleavable peptide-polyethylene glycol (PEG) conjugate. The peptide linker was used to cleave in response to the upregulated MMP-2 in the tumor microenvironment, thus exposing a positive charge via PEG-deshielding and enhancing liposomal uptake by tumor cells/vasculature. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell binding and uptake, and cytotoxicity.ResultsThe formulations had particle sizes of ~ 100-170 nm, narrow distribution (PDI ˂ 0.2), and various surface charges (- 10.2 mV to + 17.6 mV). MMP-2 overexpression was shown in several cancer cell lines (C26, 4T1, and B16F10) as compared to the normal NIH-3T3 fibroblast cells by gelatin zymography and qRT-PCR. In vitro results demonstrated enhanced antitumor efficacy of the PEG-cleavable cationic liposomes (CLs) as compared to the commercial Caelyx® (up to fivefold) and the chick chorioallantoic membrane assay showed their great antiangiogenesis potential to target and suppress tumor neovascularization. The pharmacokinetics and efficacy studies also indicated higher tumor accumulation and extended survival rates in C26 tumor-bearing mice treated with the MMP-2 cleavable CLs as compared to the non-cleavable CLs with no remarkable sign of toxicity in healthy tissues.ConclusionAltogether, the MMP-2-cleavable CLs have great potency to improve tumor-targeted drug delivery and cellular/tumor-vasculature uptake which merits further investigation.Supplementary informationThe online version contains supplementary material available at 10.1186/s12645-023-00169-8.

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Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity.

Publications

Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity.

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