Drug carriers are the substances that facilitate time-controlled delivery of drug with organ-specific targeting, protection, prolonged in vivo function.
Aoyagi T et al., in 1999, studied the peptide drug carrier, incorporation of vasopressin into nano-associates comprising poly(ethylene glycol)-poly( -aspartic acid) block copolymer 1. Bichon in 1987, got a patent for ‘Biodegradable Polypeptide and its Use for the Gradual Release of Drugs,” which describes a polyaspartate and/or polyglutamate polymer as a drug carrier. He envisions the use of polyaspartate and/or polyglutamate polymers as drug carriers wherein the drug is encapsulated or incorporated in the matrix of the polymer . Piper in 1983 explaineded a synthetic approach to poly(γ-glutamyl) conjugates of methotrexate and the use of methotrexate conjugated to 2 to 3 glutamic acid units 2. Ramsammy in 1989 discussed polyaspartic acid protects against gentamicin nephrotoxicity in rat and disclosed the use of poly-amino acids, including polyaspartic acid, to provide protection against the development of amino glycoside-induced nephrotoxicity in the rat3. Hayashi and Iwatsuki in 1990 described the preparation of copolypeptides consisting of L-aspartic acid and L-glutamic acid 4.
In a novel polypeptide drug carrier, a therapeutic compound comprising at least one drug moiety, and at least one polypeptide drug carrier moiety, the drug moiety being covalently linked to the carrier moiety, and the polypeptide drug carrier moiety comprising glutamic acid and a second amino acid selected from the group consisting of aspartic acid, alanine, asparagine, glutamine, glycine, and combinations of two or more amino acids selected from the group consisting of aspartic acid, alanine, asparagine, glutamine, and glycine .
To fabricate peptide delivery systems using polymeric drug carriers, an oligopeptide model drug, [Arg8]-vasopressin(AVP), has been incorporated into nano-associates comprising poly(ethylene glycol)-(-aspartic acid block copolymer (PEG-P(Asp)). Incorporation of the AVP was accomplished using a dialysis method. Static light scattering measurements revealed that the acid-type and mixture-type PEG-P(Asp)s formed nano-associates independently without AVP, while the salt form PEG-P(Asp) did not. High loading of AVP into acid-type PEG-P(Asp) was observed with loading levels controlled by changing the molar ratio of drug and block copolymer. Dynamic light scattering measurements showed that the acid-type PEG-P(Asp) associates sizes narrowly clustered around 150 nm. This finding suggests that associates of acid-type PEG-P(Asp) effectively incorporates peptides possibly via a hydrogen bonding interaction between the block copolymer and the peptide 1.
Mode of Action
The transport of drugs or drug delivery systems across the cell membrane is a complex biological process. In conventional carriers, the negatively charged genetic drug is mixed with a positively charged carrier. They bind together to form a complex that is unstable, especially in the bloodstream. Therefore, conventional carriers require excess positive charge to increase stability.
Many conventional carriers require high charged polymers or lipids to release the drug. Unfortunately, the high charge is toxic, and genetic anomalies have been reported, which may cause unexpected side effects. The low molecular weight protein lysozyme, that is easily filtered and reabsorbed in kidney tubular cells, was used as a carrier for renal delivery of various drugs including anti-bacterial agents. The carrier itself can add to the anti-infective effect through its lysing effect on bacterial cell walls. Albumins derivatized with various sugars were used for delivery of the anti-inflammatory drug naproxen to hepatocytes, endothelial cells and Kupffer cells. Some (glyco)-proteins, designed as a drug carrier for anti-HIV agents, exhibited an intrinsic antiviral activity even without coupling of antiviral drugs. This activity was caused by an increased negative charge of the particular (glyco)-proteins. The mechanism of action was found to be inhibition of a post binding virus/cell fusion event. The particular negatively charged albumins (NCAs) showed, in the therapeutic dose range, favorable pharmacokinetics with regard to lymphatic distribution and residence time in the blood stream 5.
Chilkoti A et al., (2002) reviewed recombinant methods for the design, synthesis and action of amino acid-based biopolymers, and summarized an approach, recursive directional ligation (RDL). Recombinant polypeptide carrier targets delivery of radionuclides, chemotherapeutics and biomolecular therapeutics to tumors. The targeted delivery system uses a thermally responsive, elastin-like polypeptide (ELP) as the drug carrier to enhance the localization of ELP-drug conjugates within a solid tumor that is heated by regional hyperthermia 6.
Biodegradable drug carriers, liposomes, albumin microspheres, soluble synthetic polymers, DNA complexes, protein-drug conjugates, and carrier erythrocytes among others have been employed as biodegradable drug carriers 5.
Polypeptide drug carrier, makes an unexpectedly good carrier for delivery of drugs, including poorly soluble drugs like anti-tumor agents.
The instant inventive conjugate (poly-glutamate/aspartate polypeptide and poly-glutamate/alanine, asparagine, glutamine, glycine) results in unexpectedly good in vivo properties when covalently linked to drugs and are superior to that found for the conjugation of drugs to other drug carriers, such as other polypeptides, including homopolymers of glutamic acid and aspartic acid.
Improves the solubility, polypeptide drug carrier improves the solubility of a drug moiety comprising the steps of covalently conjugating at least one drug moiety, and at least one polypeptide drug carrier moiety comprising glutamic acid and aspartic acid or alanine, or asparagine, or glutamine, or glycine, or combinations thereof.
2. Piper JR, Montgomery JA (1983). A synthetic approach to poly-gamma-glutamyl analogs of methotrexate. Adv Exp Med Biol., 163:95-100.
3. Ramsammy LS, Josepovitz C, Lane BP, Kaloyanides GJ (1989). Polyaspartic acid protects against gentamicin nephrotoxicity in the rat. J Pharmacol Exp Ther., 250(1):149-153. Hayashi T, Iwatsuki M (1990). Biodegradation of copoly(L-aspartic acid/L-glutamic acid) in vitro. Biopolymers, 29(3):549-557.
4. Hayashi T, Iwatsuki M (1990). Biodegradation of copoly(L-aspartic acid/L-glutamic acid) in vitro. Biopolymers, 29(3):549-57.
5. Meijer DKF, Molema G, Moolenaar F, de Zeeuw D, Swart PJ (1996). (Glyco)-protein drug carriers with an intrinsic therapeutic activity: The concept of dual targeting. Journal of controlled release, 39(2-3):163-172.
6. Chilkoti A, Dreher MR, Meyer DE (2002). Design of thermally responsive, recombinant polypeptide carriers for targeted drug delivery. Advanced Drug Delivery Reviews, 54(8-18):1093-1111.
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