Materials and methods for delivery of biological drugs

Journal name:
Nature Chemistry
Year published:
Published online


Biological drugs generated via recombinant techniques are uniquely positioned due to their high potency and high selectivity of action. The major drawback of this class of therapeutics, however, is their poor stability upon oral administration and during subsequent circulation. As a result, biological drugs have very low bioavailability and short therapeutic half-lives. Fortunately, tools of chemistry and biotechnology have been developed into an elaborate arsenal, which can be applied to improve the pharmacokinetics of biological drugs. Depot-type release systems are available to achieve sustained release of drugs over time. Conjugation to synthetic or biological polymers affords long circulating formulations. Administration of biological drugs through non-parenteral routes shows excellent performance and the first products have reached the market. This Review presents the main accomplishments in this field and illustrates the materials and methods behind existing and upcoming successful formulations and delivery strategies for biological drugs.

At a glance


  1. Biodegradable organic polymers can be used to engineer implantable depots for controlled release of biological drugs over extended periods of time.
    Figure 1: Biodegradable organic polymers can be used to engineer implantable depots for controlled release of biological drugs over extended periods of time.

    a, PLGA and PCL provide opportunities to tune the degradation rate of the implants for as long as several years. bd, Technologically there is virtually no restriction on the size of substrates and degradable matrices can be produced as nanoparticles (b), microparticles (c), and macroscopic objects (d). Panel b reproduced with permission from ref. 10, c, ref. 11 and d, ref. 12, all are from the ACS.

  2. Assembly of surface coatings.
    Figure 2: Assembly of surface coatings.

    The sequential, layer-by-layer deposition of polymers, and incorporation of biological drugs into the assembled thin films presents a facile means to engineer controlled and site-specific presentation of biologics to the cells and tissues, specifically for applications in tissue engineering and regenerative medicine. a, Polymers adsorb from solutions onto an underlying surface primed with a complementary interacting partner (polycation–polyanion, hydrogen bonding donor–acceptor). This leads to reversal of the surface properties, priming the surface for the deposition of the next polymer. Deposition cycles are repeated as necessary to achieve the desired coating thickness and can be performed on virtually any substrate with no restriction on the materials' surface chemistry, object size, or topography of the surface. Biological drugs can be immobilized into these films through adsorption during film assembly or absorption into the preformed multilayered polymer film. b, Representative polymers used in these applications include biodegradable polyamido-ester 1; biodegradable pseudo-natural polypeptides poly(lysine) 2 and poly(glutamic acid) 3; charge shifting polymer 4; hydrogen bonding donor poly(acrylic acid) 5 and complementary acceptor poly(ethylene glycol) 6; and ionic polysaccharides hyaluronic acid 7, poly(alginate) 8, and chitosan 9. Figure adapted with permission from ref. 30, ACS.

  3. Conjugation of biological drugs with synthetic non-ionic water-soluble polymers.
    Figure 3: Conjugation of biological drugs with synthetic non-ionic water-soluble polymers.

    This technology is highly successful for protecting biologics from fast proteolysis in blood, preventing their rapid renal clearance, and also decreasing recognition of the administered protein by the immune system — resulting in a significantly extended half-life of the biological drug in humans and a drastically decreased frequency of drug administration. a-b, Examples of such polymers include PEG, PVA, and PVP (a), of which PEG remains the golden standard and the polymer of choice for all but one marketed product of this kind. Conjugation of polymers to the proteins is well established using diverse tools of bioconjugation (b, N-hydroxysuccinimide derivative of PEG for a one-step conjugation to the peptidic amine groups on for example, lysine or chain terminus). Resulting conjugates are administered via injection.

  4. Recombinant techniques constitute a highly successful approach to engineer derivatives of biological drugs with markedly extended blood residence time.
    Figure 4: Recombinant techniques constitute a highly successful approach to engineer derivatives of biological drugs with markedly extended blood residence time.

    a, An expression plasmid can be engineered such that the therapeutic protein is expressed as a fused polypeptide containing the protein of interest and a non-structured polypeptide based on Pro, Ala, and/or Ser (termed PAS). Upon expression, the protein-encoding part of the polypeptide folds into the nominated therapeutic protein, whereas the PAS sequence forms a random coil. The latter serves to extend the circulation lifetime of the biological drug due to an increase in hydrodynamic volume of the conjugate (compared to the parent biological drug). aa, amino acid. b, Biological drugs can also be 'fused' through recombinant engineering (or alternatively through chemical ligation) to the XTEN protein, albumin or Fc fragment of the immunoglobulin. Of these, XTEN is a non-structured sequence and works similarly to PAS, whereas albumin and Fc extend the blood residence time of the conjugate due to physiological mechanisms of protein recycling.

  5. Physiological recycling of albumin and immunoglobulins.
    Figure 5: Physiological recycling of albumin and immunoglobulins.

    This natural mechanism to prevent degradation of and elimination of these proteins from the blood, has been adapted to become the highly successful platform for delivery of biological drugs. a, Physiological recycling upon internalization of albumin and immunoglobulins relies on the recognition of these proteins by the neonatal FcRn receptor in the lysosome upon acidification of this subcellular compartment during intracellular trafficking. Receptor bound proteins — together with the associated cargo — are exocytosed whereas all other solutes are trafficked further for processing. b, Albumin binding can be non-covalent, capitalizing on the natural propensity of albumin to bind hydrophobic solutes. Specifically, biological drugs such as peptide hormones and insulin can be functionalized with a hydrophobic (aliphatic) tail. The resulting conjugates spontaneously bind to albumin upon administration into humans.

  6. Examples of non-invasive drug administration routes.
    Figure 6: Examples of non-invasive drug administration routes.

    The routes are being developed to overcome the low bioavailability of biological drug upon administration per os, and to avoid the resulting necessity to administer biologics via injection. These routes include (but are not limited to) pulmonary, transdermal, nasal and buccal; which are schematically discussed herein together with the relative positives (in green) and negatives (in red) — specifically with regard to the delivery of biological drugs.

  7. Transdermal administration of biological drugs.
    Figure 7: Transdermal administration of biological drugs.

    This technique, specifically using transdermal microneedles penetrating the stratum corneum, is poised to be a highly versatile, non-invasive and pain-free route of administering biological drugs. Microneedles can be designed as solid miniaturized pins — to provide a temporary opening of the impermeable barrier created by the skin and allow diffusion of drugs. Coated microneedles contain the drug on their surface and deposit the payload upon contact. Dissolving microneedles contain the payload within the matrix material and release the drug upon needle dissolution. Hollow microneedles are true miniaturized analogues to serological needles for infusion of the drug. Figure adapted with permission from ref. 107, Elsevier.


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  1. Department of Chemistry, Aarhus University, Aarhus C 8000, Denmark

    • Alexander N. Zelikin
  2. iNano Interdisciplinary Nanoscience Centre, Aarhus University, Aarhus C 8000, Denmark

    • Alexander N. Zelikin
  3. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland

    • Carsten Ehrhardt &
    • Anne Marie Healy
  4. Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland

    • Carsten Ehrhardt
  5. Synthesis and Solid State Pharmaceutical Centre, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland

    • Anne Marie Healy
  6. Advanced Materials and Bioengineering Research (AMBER) Centre, Trinity College Dublin, Dublin 2, Ireland

    • Anne Marie Healy

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