Abstract
Abstract: Nano-sized carriers can help to reduce toxicity and improve clinical efficacy of drugs. Virus-like particles (VLPs) are biocompatible and biodegradable self-assembling nanoparticles, which show great promise as carriers for substances for targeted delivery and controlled release. Either chemical conjugation of physical incorporation without formation of covalent bonds is possible to load substances of interest into VLPs.Objectives: To produce VLPs from recombinant viral capsid protein (HBcAg) and test feasibility of methods of formation of chemical and physical conjugates of VLPs with substances of pharmacological interest.Methods: Virus-like particles composed from recombinant hepatitis B core antigen (HBcAg) were produced by recombinant expression in E.coli and purified by successive centrifugation through sucrose gradients. Peptide transportan 10 was synthesized and used for carbodiimide (EDC)-mediated conjugation to VLPs. Doxorubicin (DOX) was loaded into the nucleic acid-containing VLPs to form physical conjugate.Results: VLPs with chemically attached moieties of cell-penetrating peptide transportan 10 were produced. The conjugate was examined in SDS-PAGE to confirm presence of conjugation products. Conjugation efficiency (molar ration peptide/protein in the conjugate) reaches 0.5:1 (i.e. 50% of protein chains have one attached peptide moiety). The nucleic acid-containing VLPs can be loaded with the DOX forming stable non-covalent physical conjugate.Conclusion: Recombinantly expressed VLPs allow easy attaching of small molecules making them a convenient platform to develop drug carriers.
Highlights
Targeting systems for directed transport and controlled delivery of pharmaceutical substances turned out to be a breakthrough field in pharmacology
The nucleic acid-containing Virus-like particles (VLPs) can be loaded with the DOX forming stable non-covalent physical conjugate
DOX damages normal tissues and has a narrow therapeutic window meaning that any increase of dosage above marginally cytostatic level is limited by the development of systemic toxicity, cardiotoxicity and myelosuppression (Rahman, Joher, & Neefe, 1986; Bally, Nayar, Masin, Cullis, & Mayer, 1990)
Summary
Targeting systems for directed transport and controlled delivery of pharmaceutical substances turned out to be a breakthrough field in pharmacology. Nanocarrier formulations allow reducing of toxicity and improving of clinical efficacy of already known drugs. Cancer chemotherapeutics are often toxic to normal tissues. Anthracycline antibiotic doxorubicin (DOX) exhibits strong cytostatic effect and is most widely used antitumor drug. DOX damages normal tissues and has a narrow therapeutic window meaning that any increase of dosage above marginally cytostatic level is limited by the development of systemic toxicity, cardiotoxicity and myelosuppression (Rahman, Joher, & Neefe, 1986; Bally, Nayar, Masin, Cullis, & Mayer, 1990). Attempts have been made to reduce toxicity while maintaining therapeutic efficacy by coupling the DOX to biocompatible polymers (Levi-Schaffer, Bernstein, Meshorer, & Arnon, 1982; Kopecek, Rejmanova, Duncan, & Lloyd, 1985; Zunino, Pratesi, & Pezzoni, 1987) or encapsulating this drug into liposomes. Liposomal form of DOX (Doxil) has been used in clinics (Northfelt et al, 1998)
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