Biologics now constitute a significant element of available medical treatments. Owing to their clinical and commercial success, biologics are a rapidly growing class and have become a dominant therapeutic modality. Although most of the successful biologics to date are drugs that bear a peptidic backbone, ranging from small peptides to monoclonal antibodies (~500 residues; 150 kDa), new biologic modalities, such as nucleotide-based therapeutics and viral gene therapies, are rapidly maturing towards widespread clinical use. Given the rise of peptides and proteins in the pharmaceutical landscape, tremendous research and development interest exists in developing less-invasive or non-invasive routes for the systemic delivery of biologics, including subcutaneous, transdermal, oral, inhalation, nasal and buccal routes. This Review summarizes the current status, latest updates and future prospects for such delivery of peptides, proteins and other biologics.
This is a preview of subscription content
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Leader, B., Baca, Q. J. & Golan, D. E. Protein therapeutics: a summary and pharmacological classification. Nat. Rev. Drug Discov. 7, 21–39 (2008).
Fosgerau, K. & Hoffmann, T. Peptide therapeutics: current status and future directions. Drug Discov. Today 20, 122–128 (2015).
Singh, S. et al. Monoclonal antibodies: a review. Curr. Clin. Pharmacol. https://doi.org/10.2174/1574884712666170809124728 (2017).
Hamman, J. H., Enslin, G. M. & Kotzé, A. F. Oral delivery of peptide drugs. BioDrugs 19, 165–177 (2005).
Smith, P. L., Wall, D. A., Gochoco, C. H. & Wilson, G. (D) Routes of delivery: case studies:(5) Oral absorption of peptides and proteins. Adv. Drug Delivery Rev. 8, 253–290 (1992).
Jin, J.-f. et al. The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection. Patient Prefer. Adherence 9, 923 (2015).
Anselmo, A. C. & Mitragotri, S. An overview of clinical and commercial impact of drug delivery systems. J. Control. Release 190, 15–28 (2014).
Badylak, S. F. in Seminars in Cell and Developmental Biology Vol. 13, 377–383 (Elsevier, 2002).
Keizer, R. J., Huitema, A. D., Schellens, J. H. & Beijnen, J. H. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin. Pharmacokinet. 49, 493–507 (2010).
Kagan, L., Turner, M. R., Balu-Iyer, S. V. & Mager, D. E. Subcutaneous absorption of monoclonal antibodies: role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats. Pharm. Res. 29, 490–499 (2012).
Wang, W., Wang, E. & Balthasar, J. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin. Pharmacol. Ther. 84, 548–558 (2008).
Vugmeyster, Y., Xu, X., Theil, F.-P., Khawli, L. A. & Leach, M. W. Pharmacokinetics and toxicology of therapeutic proteins: advances and challenges. World J. Biol. Chem. 3, 73 (2012).
Turner, M. R. & Balu-Iyer, S. V. Challenges and opportunities for the subcutaneous delivery of therapeutic proteins. J. Pharm. Sci. 107, 1247–1260 (2018).
Fathallah, A. M., Bankert, R. B. & Balu-Iyer, S. V. Immunogenicity of subcutaneously administered therapeutic proteins — a mechanistic perspective. AAPS J. 15, 897–900 (2013).
Yasukawa, K., Sawamura, D., Sugawara, H. & Kato, N. Leuprorelin acetate granulomas: case reports and review of the literature. Br. J. Dermatol. 152, 1045–1047 (2005).
Neely, E. et al. Two-year results of treatment with depot leuprolide acetate for central precocious puberty. J. Pediatr. 121, 634–640 (1992).
Ferran, M. et al. Depot leuprorelin acetate-induced granulomas manifested as persistent suppurative nodules. Acta Dermato-Venereol. 86, 453–455 (2006).
Toole, B. P. Hyaluronan: from extracellular glue to pericellular cue. Nat. Rev. Cancer 4, 528 (2004).
Chain, E. & Duthie, E. Identity of hyaluronidase and spreading factor. Br. J. Exp. Pathol. 21, 324 (1940).
Frost, G. I. Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin. Drug Delivery 4, 427–440 (2007).
Duran-Reynals, F. Exaltation de l'activité du virus vaccinal par les extraits de certains organes. Compt Rend Soc. Biol. 9, 6–7 (1928). This is one of the earliest published reports of using hyaluronidases to improve delivery of model small molecules (dyes) and biologics (viruses).
Girish, K. & Kemparaju, K. The magic glue hyaluronan and its eraser hyaluronidase: a biological overview. Life Sci. 80, 1921–1943 (2007).
Kind, L. S. & Roffler, S. Allergic reactions to hyaluronidase. Proc. Soc. Exp. Biol. Med. 106, 734–735 (1961).
Mathews, M. B. & Dorfman, A. Inhibition of hyaluronidase. Physiol. Rev. 35, 381–402 (1955).
Schulmeister, L. Managing vesicant extravasations. Oncology 13, 284–288 (2008).
Wasserman, R. L. Recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin infusion in primary immunodeficiency diseases. Immunotherapy 9, 1035–1050 (2017).
Cui, Y., Cui, P., Chen, B., Li, S. & Guan, H. Monoclonal antibodies: formulations of marketed products and recent advances in novel delivery system. Drug Dev. Industrial Pharmacy 43, 519–530 (2017).
Rosengren, S., Souratha, J., Conway, D., Muchmore, D. B. & Sugarman, B. J. Recombinant human PH20: baseline analysis of the reactive antibody prevalence in the general population using healthy subjects. BioDrugs 32, 83–89 (2018).
Narasimhan, C., Mach, H. & Shameem, M. High-dose monoclonal antibodies via the subcutaneous route: challenges and technical solutions, an industry perspective. Ther. Delivery 3, 889–900 (2012).
Wright, J. C. & Hoffman, A. S. in Long Acting Injections and Implants 11–24 (Springer, 2012).
Dlugi, A. M., Miller, J. D. & Knittle, J. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Fertil. Steril. 54, 419–427 (1990).
Kappy, M., Stuart, T., Perelman, A. & Clemons, R. Suppression of gonadotropin secretion by a long-acting gonadotropin-releasing hormone analog (leuprolide acetate, Lupron Depot) in children with precocious puberty. J. Clin. Endocrinol. Metab. 69, 1087–1089 (1989).
Silverman, B. L. et al. A long-acting human growth hormone (Nutropin Depot®): efficacy and safety following two years of treatment in children with growth hormone deficiency. J. Pediatr. Endocrinol. Metab. 15, 715–722 (2002).
Braeckman, J. & Michielsen, D. Efficacy and tolerability of 1-and 3-month leuprorelin acetate depot formulations (Eligard®/Depo-Eligard®) for advanced prostate cancer in daily practice: a Belgian prospective non-interventional study. Arch. Med. Sci. 10, 477 (2014).
Gefvert, O. et al. Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta™) in patients with schizophrenia. Int. J. Neuropsychopharmacol. 8, 27–36 (2005).
Dunbar, J. L. et al. Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone. Alcohol. Clin. Exp. Res. 30, 480–490 (2006).
Ballav, C. & Gough, S. Bydureon: long-acting exenatide for once-weekly injection. Prescriber 23, 30–33 (2012).
Mosekilde, E., Jensen, K. S., Binder, C., Pramming, S. & Thorsteinsson, B. Modeling absorption kinetics of subcutaneous injected soluble insulin. J. Pharmacokinet. Biopharmaceut. 17, 67–87 (1989).
Berger, M. & Rodbard, D. Computer simulation of plasma insulin and glucose dynamics after subcutaneous insulin injection. Diabetes Care 12, 725–736 (1989).
Lacy, P. E., Hegre, O. D., Gerasimidi-Vazeou, A., Gentile, F. T. & Dionne, K. E. Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets. Science 254, 1782–1784 (1991).
Vegas, A. J. et al. Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice. Nat. Med. 22, 306 (2016).
Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34, 345 (2016).
Veiseh, O. et al. Size-and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat. Mater. 14, 643 (2015).
Fan, M.-Y. et al. Reversal of diabetes in BB rats by transplantation of encapsulated pancreatic islets. Diabetes 39, 519–522 (1990).
Scharp, D. W. et al. Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects. Diabetes 43, 1167–1170 (1994).
Shapiro, A. J. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230–238 (2000).
Desai, T. & Shea, L. D. Advances in islet encapsulation technologies. Nat. Rev. Drug Discov. 16, 338 (2017).
Cooper, D. K. et al. Progress in clinical encapsulated islet xenotransplantation. Transplantation 100, 2301 (2016).
Aghazadeh, Y. & Nostro, M. C. Cell therapy for type 1 diabetes: current and future strategies. Curr. Diabetes Rep. 17, 37 (2017).
Y. Li et al. In situ pneumococcal vaccine production and delivery through a hybrid biological-biomaterial vector. Sci. Adv. 2, e1600264 (2016).
Orive, G. et al. Cell encapsulation: promise and progress. Nat. Med. 9, 104 (2003).
Fliervoet, L. A. & Mastrobattista, E. Drug delivery with living cells. Adv. Drug Delivery Rev. 106, 63–72 (2016).
Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991 (2013).
Hoffman, A. S. & Stayton, P. S. Conjugates of stimuli-responsive polymers and proteins. Prog. Polym. Sci. 32, 922–932 (2007).
Chapman, A. P. PEGylated antibodies and antibody fragments for improved therapy: a review. Adv. Drug Delivery Rev. 54, 531–545 (2002).
Caliceti, P. & Veronese, F. M. Pharmacokinetic and biodistribution properties of poly (ethylene glycol)–protein conjugates. Adv. Drug Delivery Rev. 55, 1261–1277 (2003).
Alley, S. C., Okeley, N. M. & Senter, P. D. Antibody–drug conjugates: targeted drug delivery for cancer. Curr. Opin. Chem. Biol. 14, 529–537 (2010).
Sievers, E. L. & Senter, P. D. Antibody-drug conjugates in cancer therapy. Annu. Rev. Med. 64, 15–29 (2013).
Proksch, E., Brandner, J. M. & Jensen, J. M. The skin: an indispensable barrier. Exp. Dermatol. 17, 1063–1072 (2008). This is a thorough Review summarizing the excellent barrier properties of the skin.
Naik, A., Kalia, Y. N. & Guy, R. H. Transdermal drug delivery: overcoming the skin's barrier function. Pharm. Sci. Technol. Today 3, 318–326 (2000).
Prausnitz, M. R., Mitragotri, S. & Langer, R. Current status and future potential of transdermal drug delivery. Nat. Rev. Drug Discov. 3, 115–124 (2004). This is a past overview of the status of transdermal delivery technologies up to 2004.
Prausnitz, M. R. & Langer, R. Transdermal drug delivery. Nat. Biotechnol. 26, 1261 (2008).
Hansen, S. et al. The role of corneocytes in skin transport revised—a combined computational and experimental approach. Pharm. Res. 26, 1379–1397 (2009).
Bergstresser, P. R. & Taylor, J. R. Epidermal 'turnover time' — a new examination. Br. J. Dermatol. 96, 503–506 (1977).
Bouwstra, J. A. & Ponec, M. The skin barrier in healthy and diseased state. Biochim. Biophys. Acta 1758, 2080–2095 (2006).
Schoellhammer, C. M., Blankschtein, D. & Langer, R. Skin permeabilization for transdermal drug delivery: recent advances and future prospects. Expert Opin. Drug Delivery 11, 393–407 (2014).
Benson, H. A. Transdermal drug delivery: penetration enhancement techniques. Curr. Drug Delivery 2, 23–33 (2005). This is a summary of formulation-based approaches to enhance the penetration of drugs across the skin.
Arora, A., Prausnitz, M. R. & Mitragotri, S. Micro-scale devices for transdermal drug delivery. Int. J. Pharmaceut. 364, 227–236 (2008).
Sinha, V. & Kaur, M. P. Permeation enhancers for transdermal drug delivery. Drug Dev. Industrial Pharmacy 26, 1131–1140 (2000).
Williams, A. C. & Barry, B. W. Penetration enhancers. Adv. Drug Delivery Rev. 64, 128–137 (2012).
Pillai, O. & Panchagnula, R. Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers. J. Control. Release 89, 127–140 (2003).
Karande, P. & Mitragotri, S. Enhancement of transdermal drug delivery via synergistic action of chemicals. Biochim. Biophys. Acta 1788, 2362–2373 (2009).
Mitragotri, S., Blankschtein, D. & Langer, R. Ultrasound-mediated transdermal protein delivery. Science 269, 850–853 (1995).
Mitragotri, S. Healing sound: the use of ultrasound in drug delivery and other therapeutic applications. Nat. Rev. Drug Discov. 4, 255 (2005).
Chien, Y., Siddiqui, O., Sun, Y., Shi, W. & Liu, J. Transdermal iontophoretic delivery of therapeutic peptides/proteins I: insulin. Ann. NY Acad. Sci. 507, 32–51 (1987).
Prausnitz, M. R. A practical assessment of transdermal drug delivery by skin electroporation. Adv. Drug Delivery Rev. 35, 61–76 (1999).
Prausnitz, M. R. Microneedles for transdermal drug delivery. Adv. Drug Delivery Rev. 56, 581–587 (2004).
Henry, S., McAllister, D. V., Allen, M. G. & Prausnitz, M. R. Microfabricated microneedles: a novel approach to transdermal drug delivery. J. Pharm. Sci. 87, 922–925 (1998).
Kim, Y.-C., Park, J.-H. & Prausnitz, M. R. Microneedles for drug and vaccine delivery. Adv. Drug Delivery Rev. 64, 1547–1568 (2012).
Mitragotri, S. Current status and future prospects of needle-free liquid jet injectors. Nat. Rev. Drug Discov. 5, 543 (2006).
Morales, J. O. et al. Challenges and future prospects for the delivery of biologics: oral mucosal, pulmonary, and transdermal routes. AAPS J. 19, 652–668 (2017).
Gill, H. S., Denson, D. D., Burris, B. A. & Prausnitz, M. R. Effect of microneedle design on pain in human subjects. Clin. J. Pain 24, 585 (2008).
Park, J.-H., Allen, M. G. & Prausnitz, M. R. Polymer microneedles for controlled-release drug delivery. Pharm. Res. 23, 1008–1019 (2006).
Matsuzaki, K. Magainins as paradigm for the mode of action of pore forming polypeptides. Biochim. Biophys. Acta 1376, 391–400 (1998).
Kim, Y.-C., Ludovice, P. J. & Prausnitz, M. R. Transdermal delivery enhanced by magainin pore-forming peptide. J. Control. Release 122, 375–383 (2007).
Nasrollahi, S. A., Taghibiglou, C., Azizi, E. & Farboud, E. S. Cell-penetrating peptides as a novel transdermal drug delivery system. Chem. Biol. Drug Design 80, 639–646 (2012).
Chen, Y. et al. Transdermal protein delivery by a coadministered peptide identified via phage display. Nat. Biotechnol. 24, 455 (2006).
Hsu, T. & Mitragotri, S. Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc. Natl Acad. Sci. 108, 15816–15821 (2011).
Lopes, L. B. et al. Comparative study of the skin penetration of protein transduction domains and a conjugated peptide. Pharm. Res. 22, 750–757 (2005).
Desai, P., Patlolla, R. R. & Singh, M. Interaction of nanoparticles and cell-penetrating peptides with skin for transdermal drug delivery. Mol. Membrane Biol. 27, 247–259 (2010).
Chen, M. et al. Topical delivery of siRNA into skin using SPACE-peptide carriers. J. Control. Release 179, 33–41 (2014).
Menegatti, S. et al. De novo design of skin-penetrating peptides for enhanced transdermal delivery of peptide drugs. Adv. Healthcare Mater. 5, 602–609 (2016).
J. Yu et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc. Natl Acad. Sci. 112, 8260–8265 (2015). This is a recent preclinical paper describing stimuli-responsive microneedles for transdermal insulin delivery.
Y. Ye et al. Microneedles integrated with pancreatic cells and synthetic glucose-signal amplifiers for smart insulin delivery. Adv. Mater. 28, 3115–3121 (2016).
Y. Ye et al. A melanin-mediated cancer immunotherapy patch. Sci. Immunol. 2, eaan5692 (2017).
Moniruzzaman, M., Tahara, Y., Tamura, M., Kamiya, N. & Goto, M. Ionic liquid-assisted transdermal delivery of sparingly soluble drugs. Chem. Commun. 46, 1452–1454 (2010).
Agatemor, C., Ibsen, K. N., Tanner, E. E. & Mitragotri, S. Ionic liquids for addressing unmet needs in healthcare. Bioeng. Transl Med. 3, 7–25 (2018).
Novotný, M. et al. Ammonium carbamates as highly active transdermal permeation enhancers with a dual mechanism of action. J. Control. Release 150, 164–170 (2011).
Kundu, N., Roy, S., Mukherjee, D., Maiti, T. K. & Sarkar, N. Unveiling the interaction between fatty-acid-modified membrane and hydrophilic imidazolium-based ionic liquid: understanding the mechanism of ionic liquid cytotoxicity. J. Phys. Chem. B 121, 8162–8170 (2017).
Banerjee, A., Ibsen, K., Iwao, Y., Zakrewsky, M. & Mitragotri, S. Transdermal protein delivery using choline and geranate (CAGE) deep eutectic solvent. Adv. Healthc. Mater. https://doi.org/10.1002/adhm.201601411 (2017).
Goldberg, M. & Gomez-Orellana, I. Challenges for the oral delivery of macromolecules. Nat. Rev. Drug Discov. 2, 289–295 (2003). This is a detailed Review highlighting the potential of the oral delivery of biologics.
Nellans, H. N. (B) Mechanisms of peptide and protein absorption:(1) Paracellular intestinal transport: modulation of absorption. Adv. Drug Delivery Rev. 7, 339–364 (1991).
Burton, P. S., Conradi, R. A. & Hilgers, A. R. (B) Mechanisms of peptide and protein absorption:(2) Transcellular mechanism of peptide and protein absorption: passive aspects. Adv. Drug Delivery Rev. 7, 365–385 (1991).
Tsuji, A. & Tamai, I. Carrier-mediated intestinal transport of drugs. Pharm. Res. 13, 963–977 (1996).
Swaan, P. W. Recent advances in intestinal macromolecular drug delivery via receptor-mediated transport pathways. Pharm. Res. 15, 826–834 (1998).
Larhed, A. W., Artursson, P. & Björk, E. The influence of intestinal mucus components on the diffusion of drugs. Pharm. Res. 15, 66–71 (1998).
Ensign, L. M., Cone, R. & Hanes, J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv. Drug Delivery Rev. 64, 557–570 (2012).
Cone, R. A. Barrier properties of mucus. Adv. Drug Delivery Rev. 61, 75–85 (2009).
Newby, J. et al. A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchors. Nat. Commun. 8, 833 (2017).
Davis, S., Hardy, J. & Fara, J. Transit of pharmaceutical dosage forms through the small intestine. Gut 27, 886–892 (1986).
Carino, G. P. & Mathiowitz, E. Oral insulin delivery. Adv. Drug Delivery Rev. 35, 249–257 (1999).
Morishita, M. & Peppas, N. A. Is the oral route possible for peptide and protein drug delivery? Drug Discov. Today 11, 905–910 (2006).
Wilson, I. D. & Nicholson, J. K. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res. 179, 204–222 (2017).
Kolars, J. C., Watkins, P., Merion, R. M. & Awni, W. First-pass metabolism of cyclosporin by the gut. Lancet 338, 1488–1490 (1991).
Cole, E. T. et al. Enteric coated HPMC capsules designed to achieve intestinal targeting. Int. J. Pharmaceut. 231, 83–95 (2002).
Baumgartner, S., Kristl, J., Vrecer, F., Vodopivec, P. & Zorko, B. Optimisation of floating matrix tablets and evaluation of their gastric residence time. Int. J. Pharmaceut. 195, 125–135 (2000).
Theeuwes, F. OROS® osmotic system development. Drug Dev. Industrial Pharmacy 9, 1331–1357 (1983).
Harrison, G. Insulin in alcoholic solution by the mouth. Br. Med. J. 2, 1204 (1923). This is one of the first published reports on improving the oral delivery of insulin via the use of absorption enhancers.
Muranishi, S. Absorption enhancers. Crit. Rev. Ther. Drug Carrier Systems 7, 1–33 (1990).
Constantinides, P. P. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm. Res. 12, 1561–1572 (1995).
Whitehead, K. & Mitragotri, S. Mechanistic analysis of chemical permeation enhancers for oral drug delivery. Pharm. Res. 25, 1412–1419 (2008).
Fasano, A. & Uzzau, S. Modulation of intestinal tight junctions by Zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J. Clin. Invest. 99, 1158–1164 (1997).
Thanou, M., Verhoef, J. & Junginger, H. Oral drug absorption enhancement by chitosan and its derivatives. Adv. Drug Delivery Rev. 52, 117–126 (2001).
Jain, S., Kambam, S., Thanki, K. & Jain, A. K. Cyclosporine A loaded self-nanoemulsifying drug delivery system (SNEDDS): implication of a functional excipient based co-encapsulation strategy on oral bioavailability and nephrotoxicity. RSC Adv. 5, 49633–49642 (2015).
Guada, M. et al. Reformulating cyclosporine A (CsA): more than just a life cycle management strategy. J. Control. Release 225, 269–282 (2016).
Ritschel, W. Microemulsion technology in the reformulation of cyclosporine: the reason behind the pharmacokinetic properties of Neoral. Clin. Transplant. 10, 364–373 (1996).
Gursoy, R. N. & Benita, S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed. Pharmacother. 58, 173–182 (2004).
Braat, H. et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clin. Gastroenterol. Hepatol. 4, 754–759 (2006).
Brayden, D. J. & Alonso, M.-J. Oral delivery of peptides: opportunities and issues for translation. Adv. Drug Deliv. Rev. 106, 193–195 (2016).
Traverso, G. et al. Microneedles for drug delivery via the gastrointestinal tract. J. Pharm. Sci. 104, 362–367 (2015).
Eaimtrakarn, S. et al. Retention and transit of intestinal mucoadhesive films in rat small intestine. Int. J. Pharmaceut. 224, 61–67 (2001).
Eiamtrakarn, S. et al. Gastrointestinal mucoadhesive patch system (GI-MAPS) for oral administration of G-CSF, a model protein. Biomaterials 23, 145–152 (2002).
Grabovac, V., Guggi, D. & Bernkop-Schnürch, A. Comparison of the mucoadhesive properties of various polymers. Adv. Drug Delivery Rev. 57, 1713–1723 (2005).
Borchard, G. et al. The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J. Control. Release 39, 131–138 (1996).
Lehr, C.-M., Bouwstra, J. A., Schacht, E. H. & Junginger, H. E. In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int. J. Pharmaceut. 78, 43–48 (1992).
Fujita, T. et al. Improvement of intestinal absorption of human calcitonin by chemical modification with fatty acids: synergistic effects of acylation and absorption enhancers. Int. J. Pharmaceut. 134, 47–57 (1996).
Aungst, B. J. Intestinal permeation enhancers. J. Pharm. Sci. 89, 429–442 (2000).
Whitehead, K., Karr, N. & Mitragotri, S. Safe and effective permeation enhancers for oral drug delivery. Pharm. Res. 25, 1782–1788 (2008).
Matthews, D. Intestinal absorption of peptides. Physiol. Rev. 55, 537–608 (1975).
Pauletti, G. M. et al. Structural requirements for intestinal absorption of peptide drugs. J. Control. Release 41, 3–17 (1996).
Choonara, B. F. et al. A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules. Biotechnol. Adv. 32, 1269–1282 (2014).
Whitehead, K., Shen, Z. & Mitragotri, S. Oral delivery of macromolecules using intestinal patches: applications for insulin delivery. J. Control. Release 98, 37–45 (2004).
Banerjee, A., Lee, J. & Mitragotri, S. Intestinal mucoadhesive devices for oral delivery of insulin. Bioeng. Transl Med. 1, 338–346 (2016).
Gupta, V. et al. Delivery of exenatide and insulin using mucoadhesive intestinal devices. Ann. Biomed. Engineer. 44, 1993–2007 (2016).
He, H., Cao, X. & Lee, L. J. Design of a novel hydrogel-based intelligent system for controlled drug release. J. Control. Release 95, 391–402 (2004).
Colombo, P. Swelling-controlled release in hydrogel matrices for oral route. Adv. Drug Delivery Rev. 11, 37–57 (1993).
Lowman, A., Morishita, M., Kajita, M., Nagai, T. & Peppas, N. Oral delivery of insulin using pH-responsive complexation gels. J. Pharm. Sci. 88, 933–937 (1999).
Gupta, P., Vermani, K. & Garg, S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov. Today 7, 569–579 (2002).
Chirra, H. D. & Desai, T. A. Emerging microtechnologies for the development of oral drug delivery devices. Adv. Drug Delivery Rev. 64, 1569–1578 (2012).
Chirra, H. D. & Desai, T. A. Multi-reservoir bioadhesive microdevices for independent rate-controlled delivery of multiple drugs. Small 8, 3839–3846 (2012).
Tao, S. L. & Desai, T. A. Gastrointestinal patch systems for oral drug delivery. Drug Discov. Today 10, 909–915 (2005).
Banerjee, A. et al. Ionic liquids for oral insulin delivery. Proc. Natl Acad. Sci. USA 115, 7296–7301 (2018).
Davis, M. E., Chen, Z. G. & Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discov. 7, 771–782 (2008).
Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 9, 615–627 (2010).
Hoffman, A. S. The origins and evolution of “controlled” drug delivery systems. J. Control. Release 132, 153–163 (2008).
Pridgen, E. M. et al. Transepithelial transport of Fc-targeted nanoparticles by the neonatal Fc receptor for oral delivery. Sci. Transl Med. 5, 213ra167 (2013). This is a recent preclinical study that demonstrates the successful delivery of insulin via the oral delivery of targeted nanoparticles.
Yun, Y., Cho, Y. W. & Park, K. Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv. Drug Delivery Rev. 65, 822–832 (2013).
Fonseca, S. B., Pereira, M. P. & Kelley, S. O. Recent advances in the use of cell-penetrating peptides for medical and biological applications. Adv. Drug Delivery Rev. 61, 953–964 (2009).
Farokhzad, O. C. et al. Nanoparticle-aptamer bioconjugates: a new approach for targeting prostate cancer cells. Cancer Res. 64, 7668–7672 (2004).
Bannunah, A. M., Vllasaliu, D., Lord, J. & Stolnik, S. Mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: effect of size and surface charge. Mol. Pharmaceut. 11, 4363–4373 (2014).
Lai, S. K., Wang, Y.-Y. & Hanes, J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv. Drug Delivery Rev. 61, 158–171 (2009).
Lai, S. K. et al. Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc. Natl Acad. Sci. 104, 1482–1487 (2007).
Wang, Y. Y. et al. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angew. Chem. Int. Ed. Engl. 47, 9726–9729 (2008).
Anselmo, A. C. & Mitragotri, S. Nanoparticles in the clinic. Bioeng. Transl Med. 1, 10–29 (2016).
Holmgren, J. & Czerkinsky, C. Mucosal immunity and vaccines. Nat. Med. 11, S45 (2005).
Yamamoto, A. et al. Effects of various protease inhibitors on the intestinal absorption and degradation of insulin in rats. Pharm. Res. 11, 1496–1500 (1994).
Lee, V. H. & Yamamoto, A. Penetration and enzymatic barriers to peptide and protein absorption. Adv. Drug Delivery Rev. 4, 171–207 (1989).
Aguirre, T. A. et al. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv. Drug Delivery Rev. 106, 223–241 (2016).
Riglar, D. T. & Silver, P. A. Engineering bacteria for diagnostic and therapeutic applications. Nat. Rev. Microbiol. 16, 214–225 (2018).
Patton, J. S. & Byron, P. R. Inhaling medicines: delivering drugs to the body through the lungs. Nat. Rev. Drug Discov. 6, 67 (2007). This is a Review of advances in the systemic delivery of small molecules and biologics via inhalation. This Review further highlights aspects of lung physiology that affect systemic absorption.
Bosquillon, C., Lombry, C., Preat, V. & Vanbever, R. Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance. J. Control. Release 70, 329–339 (2001).
Yang, W., Peters, J. I., Williams, I. I. I., R. O. Inhaled nanoparticles — a current review. Int. J. Pharmaceut. 356, 239–247 (2008).
Van Golde, L., Batenburg, J. J. & Robertson, B. The pulmonary surfactant system: biochemical aspects and functional significance. Physiol. Rev. 68, 374–455 (1988).
Labiris, N. & Dolovich, M. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol. 56, 588–599 (2003).
van Iwaarden, F., Welmers, B., Verhoef, J., Haagsman, H. P. & Van Golde, L. Pulmonary surfactant protein A enhances the host-defense mechanism of rat alveolar macrophages. Am. J. Respir. Cell. Mol. Biol. 2, 91–98 (1990).
Geller, D. E. Comparing clinical features of the nebulizer, metered-dose inhaler, and dry powder inhaler. Respiratory Care 50, 1313–1322 (2005).
Dalby, R. & Suman, J. Inhalation therapy: technological milestones in asthma treatment. Adv. Drug Delivery Rev. 55, 779–791 (2003).
Anderson, P. J. History of aerosol therapy: liquid nebulization to MDIs to DPIs. Respiratory Care 50, 1139–1150 (2005).
Telko, M. J. & Hickey, A. J. Dry powder inhaler formulation. Respiratory Care 50, 1209–1227 (2005).
Edwards, D. A. et al. Large porous particles for pulmonary drug delivery. Science 276, 1868–1872 (1997).
Shoyele, S. A. & Cawthorne, S. Particle engineering techniques for inhaled biopharmaceuticals. Adv. Drug Delivery Rev. 58, 1009–1029 (2006).
Vanbever, R. et al. Formulation and physical characterization of large porous particles for inhalation. Pharm. Res. 16, 1735–1742 (1999).
French, D. L., Edwards, D. A. & Niven, R. W. The influence of formulation on emission, deaggregation and deposition of dry powders for inhalation. J. Aerosol Sci. 27, 769–783 (1996).
Edwards, D. A., Ben-Jebria, A. & Langer, R. Recent advances in pulmonary drug delivery using large, porous inhaled particles. J. Appl. Physiol. 85, 379–385 (1998).
Hickey, A. J. Pharmaceutical Inhalation Aerosol Technology (CRC Press, 2003).
Hickey, A. J. Inhalation Aerosols: Physical and Biological Basis for Therapy (CRC Press, 1996).
Al, M. M.-Tabakha, Future prospect of insulin inhalation for diabetic patients: The case of Afrezza versus Exubera. J. Control. Release 215, 25–38 (2015).
White, S. et al. EXUBERA®: pharmaceutical development of a novel product for pulmonary delivery of insulin. Diabetes Technol. Ther. 7, 896–906 (2005).
Hollander, P. A. et al. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care 27, 2356–2362 (2004).
Rosenstock, J., Cappelleri, J. C., Bolinder, B. & Gerber, R. A. Patient satisfaction and glycemic control after 1 year with inhaled insulin (Exubera) in patients with type 1 or type 2 diabetes. Diabetes Care 27, 1318–1323 (2004).
Skyler, J. S., Jovanovic, L., Klioze, S., Reis, J. & Duggan, W. Two-year safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 1 diabetes. Diabetes Care 30, 579–585 (2007).
Hickey, A. J. Back to the future: inhaled drug products. J. Pharm. Sci. 102, 1165–1172 (2013).
Heinemann, L. The failure of Exubera: are we beating a dead horse? J. Diabetes Sci. Technol. 2, 518–529 (2008).
Mitri, J. & Pittas, A. G. Inhaled insulin — what went wrong. Nat. Clin. Pract. Endocrinol. 5, 24 (2008).
Sélam, J.-L. Inhaled insulin: promises and concerns. J. Diabetes Sci. Technol. 2, 311–315 (2008).
Forst, T. et al. Time–action profile and patient assessment of inhaled insulin via the Exubera device in comparison with subcutaneously injected insulin aspart via the FlexPen device. Diabetes Technol. Ther. 11, 87–92 (2009).
Cavaiola, T. S. & Edelman, S. Inhaled insulin: a breath of fresh air? A review of inhaled insulin. Clin. Ther. 36, 1275–1289 (2014).
Kling, J. Sanofi to propel inhalable insulin Afrezza into market. Nat. Biotechnol. 32, 851–852 (2014).
Halliday, H. L. Surfactant replacement therapy. Pediatr. Pulmonol. 19, 96–97 (1995).
Liang, Z., Ni, R., Zhou, J. & Mao, S. Recent advances in controlled pulmonary drug delivery. Drug Discov. Today 20, 380–389 (2015).
Ruge, C. A., Kirch, J. & Lehr, C.-M. Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges. Lancet Respir. Med. 1, 402–413 (2013).
Kobayashi, S., Kondo, S. & Juni, K. Pulmonary delivery of salmon calcitonin dry powders containing absorption enhancers in rats. Pharm. Res. 13, 80–83 (1996).
Moschos, S. A. et al. Lung delivery studies using siRNA conjugated to TAT (48–60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjugate Chem. 18, 1450–1459 (2007).
Hussain, A., Arnold, J. J., Khan, M. A. & Ahsan, F. Absorption enhancers in pulmonary protein delivery. J. Control. Release 94, 15–24 (2004).
Illum, L. Nasal drug delivery — possibilities, problems and solutions. J. Control. Release 87, 187–198 (2003). This is an outstanding Review summarizing the challenges with nasal drug delivery and potential strategies to overcome these challenges for biologics.
Caon, T., Jin, L., Simões, C. M., Norton, R. S. & Nicolazzo, J. A. Enhancing the buccal mucosal delivery of peptide and protein therapeutics. Pharm. Res. 32, 1–21 (2015).
Gandhi, R. B. & Robinson, J. R. Oral cavity as a site for bioadhesive drug delivery. Adv. Drug Delivery Rev. 13, 43–74 (1994).
Hussain, M. A., Aungst, B. J., Koval, C. A. & Shefter, E. Improved buccal delivery of opioid analgesics and antagonists with bitterless prodrugs. Pharm. Res. 5, 615–618 (1988).
Shojaei, A. H. Buccal mucosa as a route for systemic drug delivery: a review. J. Pharm. Pharm. Sci. 1, 15–30 (1998).
Zhou, X. H. Overcoming enzymatic and absorption barriers to non-parenterally administered protein and peptide drugs. J. Control. Release 29, 239–252 (1994).
Klatt, N. R. et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science 356, 938–945 (2017).
Ugwoke, M. I., Verbeke, N. & Kinget, R. The biopharmaceutical aspects of nasal mucoadhesive drug delivery. J. Pharmacy Pharmacol. 53, 3–22 (2001).
Rapoport, A. & Winner, P. Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache 46, S192–S201 (2006).
Senel, S. & Hıncal, A. A. Drug permeation enhancement via buccal route: possibilities and limitations. J. Control. Release 72, 133–144 (2001).
Arora, P., Sharma, S. & Garg, S. Permeability issues in nasal drug delivery. Drug Discov. Today 7, 967–975 (2002).
Nicolazzo, J. A., Reed, B. L. & Finnin, B. C. Buccal penetration enhancers — how do they really work? J. Control. Release 105, 1–15 (2005).
Rossi, S., Sandri, G. & Caramella, C. M. Buccal drug delivery: a challenge already won? Drug Discov. Today Technol. 2, 59–65 (2005).
Boddupalli, B. M., Mohammed, Z. N., Nath, R. A. & Banji, D. Mucoadhesive drug delivery system: an overview. J. Adv. Pharm. Technol. Res. 1, 381 (2010).
Montenegro-Nicolini, M. & Morales, J. O. Overview and future potential of buccal mucoadhesive films as drug delivery systems for biologics. AAPS PharmSciTech 18, 3–14 (2017).
Morales, J. O. & Brayden, D. J. Buccal delivery of small molecules and biologics: of mucoadhesive polymers, films, and nanoparticles. Curr. Opin. Pharmacol. 36, 22–28 (2017).
Thorne, R., Pronk, G., Padmanabhan, V. & Frey Ii, W. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127, 481–496 (2004).
Thorne, R. G. et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res. 692, 278–282 (1995).
S.M. acknowledges support from the National Institutes of Health, Grant R01DK097379.
S.M. is a shareholder of, consultant to and recipient of research grants from several drug delivery, pharmaceutical and biotechnology companies, including those active in the general area of research discussed in this article. The authors are inventors on several patents in the field of drug delivery and formulations that are owned by their current or former employers. The views presented here should not be considered as endorsements of any specific product or company.
The attachment of polyethylene glycol to a biologic to shield it from the immune system and thereby increase its half-life.
- First-pass metabolism
The biological process by which the delivered biologic is metabolized by the liver or gastrointestinal tract before reaching systemic circulation.
The application of an electrical current to a biologic formulation at the surface of the skin. The current improves transport of the biologic across the skin via electrophoresis.
Phospholipid-based nanoparticles with tuneable physicochemical parameters that are designed to encapsulate and deliver biologics.
Inactive substances found in pharmaceutical formulations. Excipients can include absorption enhancers, stability enhancing agents or anticaking agents.
- Pulmonary surfactant
Lipid and protein secreted by type II alveolar cells that adsorb to the air–water interface in the lungs. Pulmonary surfactant is a required biological fluid that reduces the surface tension in lung alveoli to facilitate inhalation and exhalation.
About this article
Cite this article
Anselmo, A., Gokarn, Y. & Mitragotri, S. Non-invasive delivery strategies for biologics. Nat Rev Drug Discov 18, 19–40 (2019). https://doi.org/10.1038/nrd.2018.183
Journal of Cheminformatics (2022)
H84T BanLec has broad spectrum antiviral activity against human herpesviruses in cells, skin, and mice
Scientific Reports (2022)
Pharmaceutical Research (2022)
Bioanalytical Methods and Strategic Perspectives Addressing the Rising Complexity of Novel Bioconjugates and Delivery Routes for Biotherapeutics
Digestive Diseases and Sciences (2022)