ABSTRACT
Biodegradable poly(α-hydroxy acid) copolyesters consisting of benzyl-protected glutamic acid and carboxybenzyl-protected lysine derived blocks possess the capability to self-assemble to form stable nanoparticles in aqueous solution (pH 7.4), that are able to withhold doxorubicin, prior to its directed release in acidic solution. Such pH-responsive nanoparticles are non-toxic against a panel of human breast cancer cell lines, but demonstrated comparable toxicities to free doxorubicin when loaded with doxorubicin. Significantly, comparable efficacy to free doxorubicin was observed even against triple negative breast cancer cells, highlighting the potential of the materials generated as drug delivery vehicles for cancer treatment. Facile block copolymer deprotection resulted in a polymer that presents an altered self-assembly/disassembly profile; forming nanoparticles when stored in either acidic or alkaline solution, but undergoing self-disassembly when added to aqueous solution of pH 7.4. This second polymer highlights the considerable versatility that poly(α-hydroxy acids) inherently possess.
ABSTRACT
Biodegradable polymers have emerged as highly effective drug delivery vehicles. We combine N-carboxyanhydride and O-carboxyanhydride ring opening polymerisations to synthesise a poly(amino acid)-polyester graft copolymer capable of encapsulating, and subsequently releasing doxorubicin via acid-mediated hydrolysis. Consequently, the nanoparticles detailed are extremely promising vehicles for the controlled delivery of chemotherapeutic agents.
Subject(s)
Doxorubicin/chemistry , Drug Carriers/chemistry , Nanoparticles/chemistry , Peptides/chemistry , Polyesters/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biodegradable Plastics/chemical synthesis , Biodegradable Plastics/chemistry , Biodegradable Plastics/toxicity , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Carriers/chemical synthesis , Drug Carriers/toxicity , Drug Liberation , Humans , Hydrolysis , Mice , Nanoparticles/toxicity , Particle Size , Peptides/chemical synthesis , Peptides/toxicity , Polyesters/chemical synthesis , Polyesters/toxicityABSTRACT
The glucoseamine-initiated ring-opening polymerisation of amino acid N-carboxyanhydrides and O-carboxanhydrides to yield amphiphilic block copolymers that are capable of self-assembly in aqueous solution to form well-defined, glucose-presenting, particles is reported. The particles formed are susceptible to enzyme-mediated (lipase and protease) and pH-induced degradation, and can selectively bind the lectin concanavalin A. Consequently, such glycoparticles are of significance for the controlled release of payload molecules in response to an acidic environment, for instance cancerous tissue, and upon interaction with target enzymes.
Subject(s)
Anhydrides/chemistry , Drug Carriers/chemistry , Glucose/chemistry , Peptides/chemistry , Polyesters/chemistry , Sarcosine/analogs & derivatives , Biodegradable Plastics , Concanavalin A/chemistry , Drug Carriers/chemical synthesis , Drug Liberation , Humans , Hydrogen-Ion Concentration , Lectins/chemistry , Lipase/chemistry , Nanoparticles/chemistry , Particle Size , Peptide Hydrolases/chemistry , Peptides/chemical synthesis , Polyesters/chemical synthesis , Polyethylene Glycols/chemistry , Polymerization , Rhodamines/chemistry , Sarcosine/chemical synthesis , Sarcosine/chemistry , Surface PropertiesABSTRACT
Organogels prepared with vegetable oils as the liquid organic phase present an excellent platform for the controlled delivery of hydrophobic guest molecules. We disclose a graft copolymer comprised of a poly(L-serine) backbone linked to alkane side-chains by hydrolytically susceptible ester bonds, that is capable of gelating edible safflower oil. The thermoresponsive organogel formed, which is non-cytotoxic, is capable of withholding guest molecules before undergoing targeted disassembly upon incubation in solutions of acidic pH, permitting the directed release of payload molecules. The presented material offers an extremely promising candidate for the controlled delivery of hydrophobic agents within acidic environments, such as cancer tumour sites.
Subject(s)
Drug Carriers/chemistry , Gels/chemistry , Plant Oils/chemistry , Animals , Cell Line , Cell Survival/drug effects , Drug Carriers/metabolism , Drug Carriers/toxicity , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Mice , Polymers/chemistry , Rhodamines/chemistry , Rhodamines/metabolism , Spectroscopy, Fourier Transform InfraredABSTRACT
The direct grafting of amphiphilic macromolecules by sequential n-carboxyanhydride ring-opening polymerisation (NCA ROP) from a therapeutic initiator enables the formation of monodisperse drug-containing micelles. The subsequent enzyme-mediated hydrolysis of the peptide component permits the programmed release of the encapsulated drug molecules, demonstrating a controlled drug delivery platform that negates any challenging payload loading procedures.
