18-01-2013, 02:26 PM
Bioconjugation
Bioconjugation.pdf (Size: 839.6 KB / Downloads: 99)
INTRODUCTION
In modern drug delivery systems, attachment of the cellular and subcellular targeting moieties, delivery enhancing molecules or functional entities to drugs is becoming an important approach (1). In recent years, increasing studies are devoted to the development of the drug delivery system and targeting of drug. The present drug delivery systems have poor specificity and dose-limited toxicity for treatment of diseases. So that, there is increasing need of selective delivery can be brought through a bioconjugation approach. Bioconjugation has recently been applied to the delivery of drugs with simple or complex structures, including peptides, enzymes and oligonucleotides. Bioconjugate is an advanced concept that opens new way for drug delivery and at the same time opens new possibilities for safe and effective therapy. Bioconjugation is a novel approach, which is usually exploited to improve the biopharmaceutical aspects of a bioactive as well as temporal distribution in the living environment. In the last few decades, many efforts have been devoted to understanding the biological machinery that rules the physiological activities of cells. An advanced knowledge of cell biology and the biochemical mechanisms that underlie pathological conditions has facilitated the development of new, efficient drugs for targeted therapies.
Now a day’s pharmaceutical and biotechnological based companies are seeking for more targeted therapies and clinically more efficacious drugs, by creating a successful drug conjugate having desirable biopharmaceutical properties. Bioconjugtes will help for the novel delivery of drugs. Several examples, including antibodies or antibody fragments e.g. infliximab, rituximab (Rituxam®), enzymes (e.g. asparaginase and adenosine deaminase), vaccines and other biomodulators are currently available in market and others are under investigation. Now recently, certain bioconjugates are reported with bioconjugated nanoparticles for biosensing and bioimaging incorporate cell staining, DNA detection, separation and recombination relevance in DNA protection, bioconjugtes have gained importance in enzyme therapy, gene therapy, insulin therapy, cancer therapy and management of AIDS with the interception of minimal side effects. Bioconjugation can be a novel approach for the targeting of therapeutic agents, also have immense potential and extend a promising future for delivery of drugs. In the future, bioconjugated drugs will eventually fulfill promise of specific delivery of drugs to target, thus avoiding dose-limiting toxicity of drugs that occurs as a result of its effects on normal cells.
Bioconjugates: A novel approach for targeted drug delivery
BIOCONJUGATES
Bioconjugation is novel approach which involves coupling two biomolecules together in a covalent linkage. “Bioconjugation is the linking of two biomolecules which forms a hybrid molecule; bioconjugates retains properties of each individual component, yet yielding a single entity with two complementary functions”. It is simply joining two molecular functions by chemical means. It includes the conjugation of antibodies (and their fragments), nucleic acids (and their analogues), other molecules such as receptor binding protein, hormones, peptides with each other or with molecules which add useful properties such as drugs, toxins, inhibitors, enzymes and ligands. These are formed by reacting of complementary functional group of two molecules which formed desire bioconjugates. In figure 1 illustrates the formation of bioconjugates by linking of active agent with targeting moiety with the help of linker.
Targeting moiety Linker active agent Bioconjugate
Common types of bioconjugates are amine coupling of lysine amino acid residues (typically through amine-reactive succinimydyl ester, sulphahydryl coupling of cysteine residues) via a sulfhydryl-reactive malenaimide and photochemical initiated free radical reactions, which have broader reactivity. The most common bioconjugations are coupling of a small molecule (such as biotin or fluorescent dye) to a protein, or protein-protein conjugations, such as the coupling of an antibody to an enzyme. Other less common molecules used in bioconjugation are oligosaccharides, nucleic acid synthetic polymers such as 2-methacryloyloxyethyl phosphorylcholine (MPC) and antibody-drugs bioconjugates such as ozoganacin which an active area of research in the pharmaceutical industry. Site specific delivery may be obtained by tailoring the conjugate as an inactive prodrug and designing polymer drug linkages susceptible to cleavage by specific enzymes or pH. These prodrugs substantially change the mechanisms of cellular entry, pharmacokinetic disposition and ultimately target the drug. In bioconjugates the incorporated bimolecular targeting moiety helps in the biorecognition of conjugates by target tissues or cells where the active therapeutic agent shows its action.
Bioconjugates: A novel approach for targeted drug delivery
. Importance of Bioconjugates Targeting of drug delivery to the specific group of cells offers an attractive strategy to minimize the undesirable side effects of the drugs and achieve the maximum therapeutic effects in lower dose (2). The present drug delivery has the poor specificity for targeting of drugs to the specific part due to which it is showing poor efficacy and the undesirable side effects for many drugs. So the bioconjugates will be helpful for targeting of the drugs selectively and specifically to require organs and to specific cells (3). The bioconjugate is made up of the biomolecules, active agent and linkers who are joins these two molecules covalently will make bioconjugates. So bioconjugation technique explores new vistas of drug delivery and opens new possibilities for safe and effective drugs therapy.
Advantages
Bioconjugates can stabilize labile drugs from chemical or proteolytic degradation. E.g. prevent degradation of asparaginase due to asparagin synthtase (3, 4).
Bioconjugates can reduce the immunogenicity of drugs or mask antigenic site of drugs. E.g. conjugation of L-asparaginase with PEG through targeting moiety, enzyme L-asparaginase is used for the treatment of acute lymphoblastic leukaemia (3, 4).
Bioconjugates alter drugs pharmacokinetics and biodistribution, increased body residence time, increasing in mass that reduces kidney ultra filtration e.g. drug-antibody conjugate with hydrazone linker have half life 2.6 days in human (3, 5, 6).
Drug penetration occurs by endocytosis, and carries the drugs directly to the target sites. E.g. conjugates through disulfide linker (1, 3).
Because of the targeting, the side effects will be lower and give a wider therapeutic window.
In addition, drug bioconjugation offers the important commercial advantage of extending the patent life of a drug.
. Disadvantages
It increases the molecular weight of the drugs so it have low diffusivity, and uptake via permeation through membrane is very low which affects the pharmacokinetics, dynamics and metabolism properties of drugs (7).
Bioconjugates: A novel approach for targeted drug delivery
COMPONENTS OF BIOCONJUGATES
Bioconjugates are made up of active agents, biorecognition element (targeting moiety), linker and/or carrier molecule.
3.1. Active Agents
Active agents which are drug substance or diagnostic agents and used for treatment or any other specific purpose e.g. purification, detection etc. Now a day’s most of bioconjugates of active agents are under clinical trials which can be used for efficient cancer treatment in future.