Controlled Delivery Systems: From Pharmaceuticals to Cells and Genes

ABSTRACTDuring the last few decades, a fair amount of scientific investigation has focused on developing novel and efficient drug delivery systems. According to different clinical needs, specific biopharmaceutical carriers have been proposed. Micro- and nanoparticulated systems, membranes and films, gels and even microelectronic chips have been successfully applied in order to deliver biopharmaceuticals via different anatomical routes. The ultimate goal is to deliver the potential drugs to target tissues, where regeneration or therapies (chemotherapy, antibiotics, and analgesics) are needed. Thereby, the bioactive molecule should be protected against environmental degradation. Delivery should be achieved in a dose- and time-correct manner. Drug delivery systems (DDS) have been conceived to provide improvements in drug administration such as ability to enhance the stability, absorption and therapeutic concentration of the molecules in combination with a long-term and controlled release of the drug. Moreover, the adverse effects related with some drugs can be reduced, and patient compliance could be improved. Recent advances in biotechnology, pharmaceutical sciences, molecular biology, polymer chemistry and nanotechnology are now opening up exciting possibilities in the field of DDS. However, it is also recognized that there are several key obstacles to overcome in bringing such approaches into routine clinical use. This review describes the present state-of-the-art DDS, with examples of current clinical applications, and the promises and challenges for the future in this innovative field.

[1]  R. Reis,et al.  Preparation and characterization of starch-poly-epsilon-caprolactone microparticles incorporating bioactive agents for drug delivery and tissue engineering applications. , 2009, Acta biomaterialia.

[2]  Marilena Loizidou,et al.  Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. , 2009, Trends in pharmacological sciences.

[3]  Gorka Orive,et al.  History, challenges and perspectives of cell microencapsulation. , 2004, Trends in biotechnology.

[4]  Lisa Brannon-Peppas,et al.  Active targeting schemes for nanoparticle systems in cancer therapeutics. , 2008, Advanced drug delivery reviews.

[5]  Jörg A Auer,et al.  Localized insulin-like growth factor I delivery to enhance new bone formation. , 2003, Bone.

[6]  R. Langer,et al.  Effects of low-frequency ultrasound on the transdermal permeation of mannitol: comparative studies with in vivo and in vitro skin. , 2002, Journal of pharmaceutical sciences.

[7]  R L Reis,et al.  Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts) , 2008, Journal of tissue engineering and regenerative medicine.

[8]  E. Lavelle,et al.  Delivery systems and adjuvants for oral vaccines , 2006, Expert opinion on drug delivery.

[9]  Schipper,et al.  Cyclodextrins in nasal drug delivery. , 1999, Advanced drug delivery reviews.

[10]  S. Sakai,et al.  Development of alginate–agarose subsieve-size capsules for subsequent modification with a polyelectrolyte complex membrane , 2006 .

[11]  J. Susset,et al.  Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group. , 1999, The Journal of urology.

[12]  J. Huard,et al.  Muscle-derived stem cells for tissue engineering and regenerative therapy. , 2007, Biomaterials.

[13]  Iqbal,et al.  Starch capsules: an alternative system for oral drug delivery. , 2000, Pharmaceutical science & technology today.

[14]  K. Johnston,et al.  Templated Open Flocs of Nanorods for Enhanced Pulmonary Delivery with Pressurized Metered Dose Inhalers , 2008, Pharmaceutical Research.

[15]  T. Abribat,et al.  The rise and rise of drug delivery , 2005, Nature Reviews Drug Discovery.

[16]  Gordana Vunjak-Novakovic,et al.  Bioactive hydrogel scaffolds for controllable vascular differentiation of human embryonic stem cells. , 2007, Biomaterials.

[17]  Gorka Orive,et al.  Delivering growth factors for therapeutics. , 2008, Trends in pharmacological sciences.

[18]  C. Pinilla,et al.  Targeting approaches to oral drug delivery , 2002, Expert opinion on biological therapy.

[19]  J. Thipphawong,et al.  Safety and pharmacokinetics of inhaled morphine delivered using the AERx system in patients with moderate-to-severe asthma. , 2004, International journal of clinical pharmacology and therapeutics.

[20]  Samir Mitragotri,et al.  Micro-scale devices for transdermal drug delivery. , 2008, International journal of pharmaceutics.

[21]  A. Kanai,et al.  Nitric oxide synthase gene therapy for erectile dysfunction: comparison of plasmid, adenovirus, and adenovirus-transduced myoblast vectors. , 2001, Molecular urology.

[22]  X. Wu,et al.  Temperature and pH-responsive polymeric composite membranes for controlled delivery of proteins and peptides. , 2004, Biomaterials.

[23]  Ludovico Cademartiri,et al.  Nanofabrication by self-assembly , 2009 .

[24]  Lorenz Meinel,et al.  Silk fibroin spheres as a platform for controlled drug delivery. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[25]  Baolin Guo,et al.  Preparation and properties of a pH/temperature-responsive carboxymethyl chitosan/poly(N-isopropylacrylamide)semi-IPN hydrogel for oral delivery of drugs. , 2007, Carbohydrate research.

[26]  G. Bernstein Delivery of insulin to the buccal mucosa utilizing the RapidMist™ system , 2008 .

[27]  D. Mooney,et al.  Hydrogels for tissue engineering. , 2001, Chemical reviews.

[28]  Po‐Chang Chiang,et al.  Fluticasone and budesonide nanosuspensions for pulmonary delivery: preparation, characterization, and pharmacokinetic studies. , 2008, Journal of pharmaceutical sciences.

[29]  R. Langer,et al.  Designing materials for biology and medicine , 2004, Nature.

[30]  Cheryl H. Dean,et al.  Cutaneous Delivery of a Live, Attenuated Chimeric Flavivirus Vaccines against Japanese Encephalitis (ChimeriVaxTM-JE) in Non-Human Primates , 2005, Human vaccines.

[31]  A. Berkowitz,et al.  Novel Drug Delivery Systems: Future Directions , 2009, The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses.

[32]  Gabriela A Silva,et al.  Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. , 2007, Advanced drug delivery reviews.

[33]  S. Sakai,et al.  Production of cell‐enclosing hollow‐core agarose microcapsules via jetting in water‐immiscible liquid paraffin and formation of embryoid body‐like spherical tissues from mouse ES cells enclosed within these microcapsules , 2008, Biotechnology and bioengineering.

[34]  Gorka Orive,et al.  Techniques: new approaches to the delivery of biopharmaceuticals. , 2004, Trends in pharmacological sciences.

[35]  Robert Langer,et al.  Advances in Biomaterials, Drug Delivery, and Bionanotechnology , 2003 .

[36]  L. Babiuk,et al.  Microparticles for oral delivery of vaccines , 2005, Expert opinion on drug delivery.

[37]  D J Mooney,et al.  Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis , 2007, Journal of thrombosis and haemostasis : JTH.

[38]  K. Balos,et al.  Encapsulation and osteoinduction of human periodontal ligament fibroblasts in chitosan-hydroxyapatite microspheres. , 2007, Journal of biomedical materials research. Part A.

[39]  G. Liversidge,et al.  Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs , 1995 .

[40]  Takuro Niidome,et al.  PEG-modified gold nanorods with a stealth character for in vivo applications. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[41]  Mark R Prausnitz,et al.  Microneedles permit transdermal delivery of a skin-impermeant medication to humans , 2008, Proceedings of the National Academy of Sciences.

[42]  Mark G. Allen,et al.  Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Brewster,et al.  Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. , 1996, Journal of pharmaceutical sciences.

[44]  A. Okyar,et al.  Ondansetron-loaded chitosan microspheres for nasal antiemetic drug delivery: an alternative approach to oral and parenteral routes , 2010, Drug development and industrial pharmacy.

[45]  Vladimir P Torchilin,et al.  Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. , 2006, Annual review of biomedical engineering.

[46]  Anil Kumar Bajpai,et al.  Responsive polymers in controlled drug delivery , 2008 .

[47]  Javad Parvizi,et al.  Selfprotective smart orthopedic implants , 2007, Expert review of medical devices.

[48]  P. Brunetti,et al.  Standard technical procedures for microencapsulation of human islets for graft into nonimmunosuppressed patients with type 1 diabetes mellitus. , 2006, Transplantation proceedings.

[49]  D. Mooney,et al.  Transplanted Endothelial Cells Enhance Orthotopic Bone Regeneration , 2006, Journal of dental research.

[50]  M. Elmazar,et al.  Oral delivery of insulin from enteric-coated capsules containing sodium salicylate: effect on relative hypoglycemia of diabetic beagle dogs. , 2002, International journal of pharmaceutics.

[51]  P. Shah Use of Nanotechnologies for Drug Delivery , 2006 .

[52]  J. Huard,et al.  Muscle-based gene therapy and tissue engineering for the musculoskeletal system. , 2001, Drug discovery today.

[53]  Freddie H. Fu,et al.  Gene therapy and the future of cartilage repair , 2001 .

[54]  G. Orive,et al.  Cell microencapsulation technology for biomedical purposes: novel insights and challenges. , 2003, Trends in pharmacological sciences.

[55]  S. Sakai,et al.  Agarose–gelatin conjugate for adherent cell-enclosing capsules , 2007, Biotechnology Letters.

[56]  M. Alaoui-Ismaili,et al.  Design of second generation therapeutic recombinant bone morphogenetic proteins. , 2009, Cytokine & growth factor reviews.

[57]  You Han Bae,et al.  Polymer Architecture and Drug Delivery , 2006, Pharmaceutical Research.

[58]  E. Cevher,et al.  Nasal Delivery of High Molecular Weight Drugs , 2009, Molecules.

[59]  G. Lust,et al.  Insulin-like growth factor-I enhances cell-based repair of articular cartilage. , 2002, The Journal of bone and joint surgery. British volume.

[60]  Antonios G Mikos,et al.  In vitro release of transforming growth factor-beta 1 from gelatin microparticles encapsulated in biodegradable, injectable oligo(poly(ethylene glycol) fumarate) hydrogels. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[61]  U Conte,et al.  Modulation of the dissolution profiles from Geomatrix multi-layer matrix tablets containing drugs of different solubility. , 1996, Biomaterials.

[62]  M. Ferrari,et al.  Drug Delivery Systems , 2006 .

[63]  David L Kaplan,et al.  Osteogenesis by human mesenchymal stem cells cultured on silk biomaterials: comparison of adenovirus mediated gene transfer and protein delivery of BMP-2. , 2006, Biomaterials.

[64]  H. Maibach,et al.  Percutaneous Penetration Enhancers: An Overview , 2007, Skin Pharmacology and Physiology.

[65]  T. Gill,et al.  Effects of auricular chondrocyte expansion on neocartilage formation in photocrosslinked hyaluronic acid networks. , 2006, Tissue engineering.

[66]  D. Kohane,et al.  HYDROGELS IN DRUG DELIVERY: PROGRESS AND CHALLENGES , 2008 .

[67]  Yasuhiko Tabata,et al.  Enhanced ectopic bone formation using a combination of plasmid DNA impregnation into 3-D scaffold and bioreactor perfusion culture. , 2006, Biomaterials.

[68]  S. Davis,et al.  Pharmacokinetics and Acute Safety of Inhaled Testosterone in Postmenopausal Women , 2005, Journal of clinical pharmacology.

[69]  Wijaya Martanto,et al.  Transdermal Delivery of Insulin Using Microneedles in Vivo , 2004, Pharmaceutical Research.

[70]  Gorka Orive,et al.  Drug delivery in biotechnology: present and future. , 2003, Current opinion in biotechnology.

[71]  S. Feng,et al.  In vitro and in vivo studies on vitamin E TPGS-emulsified poly(D,L-lactic-co-glycolic acid) nanoparticles for paclitaxel formulation. , 2006, Biomaterials.

[72]  P. Laurent,et al.  Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system. , 2007, Vaccine.

[73]  K Remberger,et al.  Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I) , 2005, Gene Therapy.

[74]  Henry,et al.  Microfabricated microneedles: A novel approach to transdermal drug delivery , 1999, Journal of pharmaceutical sciences.

[75]  S. Lyu,et al.  A novel method of encapsulating and cultivating adherent mammalian cells within collagen microcarriers , 2007, Biotechnology and bioengineering.

[76]  R. Reis,et al.  Drug delivery therapies I General trends and its importance on bone tissue engineering applications , 2002 .

[77]  A. Shrivastava,et al.  Development and Characterization of Mucoadhesive Microspheres Bearing Salbutamol for Nasal Delivery , 2004, Drug delivery.

[78]  J. Hadgraft,et al.  Modified-Release Drug Delivery Technology , 2002 .

[79]  Giovanni Luca,et al.  Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. , 2006, Diabetes care.

[80]  Freddie H. Fu,et al.  Gene therapy and tissue engineering for sports medicine , 2003, The journal of gene medicine.

[81]  Implants in Drug Delivery , 2011 .

[82]  G. Liversidge,et al.  Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats , 1995 .

[83]  S. Scheindlin Transdermal drug delivery: PAST, PRESENT, FUTURE. , 2004, Molecular interventions.

[84]  Cesario Z. Cerna,et al.  Effect of Nanonization on Absorption of 301029: Ex Vivo and In Vivo Pharmacokinetic Correlations Determined by Liquid Chromatography/Mass Spectrometry , 2002, Pharmaceutical Research.

[85]  P. Zambelli,et al.  Orthopedic implant used as drug delivery system: clinical situation and state of the research. , 2008, Current Drug Delivery.

[86]  Philippe Rogueda Novel hydrofluoroalkane suspension formulations for respiratory drug delivery , 2005, Expert opinion on drug delivery.

[87]  David J. Mooney,et al.  Spatio–temporal VEGF and PDGF Delivery Patterns Blood Vessel Formation and Maturation , 2007, Pharmaceutical Research.

[88]  S. Mitragotri,et al.  Current status and future potential of transdermal drug delivery , 2004, Nature Reviews Drug Discovery.

[89]  Gorka Orive,et al.  Cell microencapsulation technology: towards clinical application. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[90]  S. Waldman,et al.  The Pharmacokinetics of Nebulized Nanocrystal Budesonide Suspension in Healthy Volunteers , 2004, Journal of clinical pharmacology.

[91]  Barrett E. Rabinow,et al.  Nanosuspensions in drug delivery , 2004, Nature Reviews Drug Discovery.

[92]  M. Cormier,et al.  Transdermal Delivery of Antisense Oligonucleotides with Microprojection Patch (macroflux®) Technology , 2001, Pharmaceutical Research.

[93]  M. Allen,et al.  Microfabricated microneedles for gene and drug delivery. , 2000, Annual review of biomedical engineering.

[94]  R. Hayes,et al.  Effect of inhaled insulin on patient-reported outcomes and treatment preference in patients with type 1 diabetes* , 2007, Current medical research and opinion.

[95]  V V Ranade,et al.  Drug Delivery Systems 4. Implants in Drug Delivery , 1990, Journal of clinical pharmacology.

[96]  T. Chang,et al.  Therapeutic applications of polymeric artificial cells , 2005, Nature Reviews Drug Discovery.

[97]  E. Schwarz,et al.  Review: gene- and stem cell-based therapeutics for bone regeneration and repair. , 2007, Tissue engineering.

[98]  L. R. Kaiser The future of multihospital systems. , 1992, Topics in health care financing.

[99]  I. Quijada-Garrido,et al.  A novel controlled drug delivery system based on pH-responsive hydrogels included in soft gelatin capsules. , 2010, Acta biomaterialia.

[100]  K. Jain Strategies and technologies for drug delivery systems , 1998 .

[101]  P. Vos,et al.  Advances and Barriers in Mammalian Cell Encapsulation for Treatment of Diabetes , 2006 .

[102]  U. Banakar,et al.  Implantable Drug Delivery , 1994, Journal of biomaterials applications.

[103]  Robert Langer,et al.  Transdermal drug delivery , 2008, Nature Biotechnology.

[104]  E. Versi,et al.  Dry Mouth With Conventional and Controlled‐Release Oxybutynin in Urinary Incontinence , 2000, Obstetrics and gynecology.

[105]  M. Sangalli,et al.  Oral pulsatile drug delivery systems , 2005, Expert opinion on drug delivery.

[106]  Adrian C. Williams,et al.  Penetration enhancers. , 2004, Advanced drug delivery reviews.

[107]  J. Huard,et al.  Gene therapy strategies for urological dysfunction. , 2001, Trends in molecular medicine.

[108]  Paolo Colombo,et al.  Multi-layered hydrophilic matrices as constant release devices (GeomatrixTM Systems) , 1993 .

[109]  Carol Tucker-Burden,et al.  Immune responses to an encapsulated allogeneic islet beta-cell line in diabetic NOD mice. , 2006, Biochemical and biophysical research communications.

[110]  R. Reis,et al.  Drug delivery therapies II. Strategies for delivering bone regenerating factors , 2002 .

[111]  R. Duncan The dawning era of polymer therapeutics , 2003, Nature Reviews Drug Discovery.

[112]  Vladimir R Muzykantov,et al.  Polymeric carriers: role of geometry in drug delivery. , 2008, Expert opinion on drug delivery.

[113]  M. Cormier,et al.  Macroflux Technology for Transdermal Delivery of Therapeutic Proteins and Vaccines , 2002 .

[114]  Denis Dufrane,et al.  Six-Month Survival of Microencapsulated Pig Islets and Alginate Biocompatibility in Primates: Proof of Concept , 2006, Transplantation.

[115]  S. Chan,et al.  Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetry. , 2002, Journal of pharmaceutical sciences.

[116]  P. Robbins,et al.  Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy , 2005, Gene Therapy.

[117]  M. Hatziapostolou,et al.  Anticancer activity of cisplatin-loaded PLGA-mPEG nanoparticles on LNCaP prostate cancer cells. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[118]  Antonios G Mikos,et al.  Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model. , 2008, Bone.

[119]  J. Swanson,et al.  Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies. , 2003, Archives of general psychiatry.

[120]  K. Boekelheide,et al.  Extensive neuroprotection by choroid plexus transplants in excitotoxin lesioned monkeys , 2006, Neurobiology of Disease.

[121]  C. Rhodes,et al.  Coatings for controlled-release drug delivery systems. , 1998, Drug development and industrial pharmacy.

[122]  R. Tuan,et al.  Concepts in gene therapy for cartilage repair. , 2008, Injury.

[123]  Gorka Orive,et al.  Encapsulated cell technology: from research to market. , 2002, Trends in biotechnology.

[124]  Thomas H. LaBean,et al.  Nanofabrication by DNA self-assembly , 2009 .

[125]  Teerapol Srichana,et al.  Development of a pH-responsive drug delivery system for enantioselective-controlled delivery of racemic drugs. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[126]  M. Allen,et al.  Lack of Pain Associated with Microfabricated Microneedles , 2001, Anesthesia and analgesia.

[127]  N. Peppas,et al.  Bioadhesives for optimization of drug delivery. , 1995, Journal of drug targeting.

[128]  Yi Hong,et al.  Covalently crosslinked chitosan hydrogel: properties of in vitro degradation and chondrocyte encapsulation. , 2007, Acta biomaterialia.

[129]  S. Werner,et al.  Regulation of wound healing by growth factors and cytokines. , 2003, Physiological reviews.

[130]  M. Machluf,et al.  Alginate–chitosan complex coacervation for cell encapsulation: Effect on mechanical properties and on long‐term viability , 2006, Biopolymers.

[131]  Kaiser Lr The future of multihospital systems. , 1992 .

[132]  Y. Tabata,et al.  Non-viral gene transfection technologies for genetic engineering of stem cells. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[133]  Johnny Huard,et al.  The use of ex vivo gene transfer based on muscle-derived stem cells for cardiovascular medicine. , 2002, Trends in cardiovascular medicine.