3 Drug Formulations
3.8 Cells as Vehicles for Drug Delivery
3.8.1 Cell-Mediated Gene Therapy
Table 8
Methods of gene therapy
Gene transfer
Chemical: calcium phosphate transfection Physical
Electroporation Gene gun
Transduction with recombinant virus vectors Adeno-associated virus
Adenovirus
Herpes simplex virus Lentivirus
Moloney murine leukemia virus Retroviral vectors
Vaccinia virus Other viruses
Nonviral vectors for gene therapy Liposomes
Ligand–polylysine–DNA complexes
Dendrimers and other polycationic polymers Synthetic peptide complexes
Artifi cial viral vectors Artifi cial chromosomes
Use of microorganisms as oncolytic agents Bacteria for gene delivery
Viral oncolysis Cell/gene therapy
Administration of cells modifi ed ex vivo
Implantation of genetically engineered cells to produce therapeutic substances Gene/DNA administration
Direct injection of naked DNA or genes: systemic or at target site Receptor-mediated endocytosis
Use of refi ned methods of drug delivery, e.g., microspheres
(continued)
RBCs represent naturally designed carriers for intravascular drug delivery, characterized by unique longevity in the bloodstream, biocompatibility, and safe physiological mechanisms for metabo-lism [ 22 ]. Several protocols of infusion of RBC-encapsulated drugs are being explored in patients. Delivery of drugs, particularly those targeting phagocytic cells and those that must act within the vascu-lar lumen, may benefi t from carriage by RBCs. Two strategies for RBC drug delivery are (1) encapsulation into isolated RBCs ex vivo followed by infusion in compatible recipients and (2) coupling of drugs to the surface of RBCs, e.g., those regulating immune response. RBC drug delivery by injection of therapeutics conju-gated with fragments of antibodies provides safe anchoring of car-goes to circulating RBC, without the need for ex vivo modifi cation and infusion of RBC.
When RBCs are placed in a hypotonic medium, they swell with rupture of the membrane and formation of pores. This allows encapsulation of 25 % of the drug or enzyme in solution.
3.8.2 RBCs as Drug Delivery Vehicles
Gene regulation
Regulation of expression of delivered genes in target cells by locus control region technology
Light-activated gene therapy
Molecular switch to control expression of genes in vivo Promoter element-triggered gene therapy
Repair of defective genes
Involves correction of the gene in situ, e.g., chimeraplasty Gene repair mediated by single- stranded oligonucleotides Gene replacement
Excision or replacement of the defective gene by a normal gene Spliceosome-mediated RNA trans-splicing
Inhibition of gene expression Antisense oligodeoxynucleotides Antisense RNA
Ribozymes
RNA interference: delivery of small interfering RNAs (siRNAs) © Jain PharmaBiotech
Table 8 (continued)
The membrane is resealed by restoring the tonicity of the solution.
Potential uses of loaded RBCs as drug delivery systems are:
● They are biodegradable and non-immunogenic.
● They can be modifi ed to change their resident circulation time;
depending on their surface, cells with little surface damage can circulate for a longer time.
● Entrapped drug is shielded from immunological detection and external enzymatic degradation.
● The system is relatively independent of the physicochemical properties of the drug.
The drawbacks of using RBCs are that the damaged RBCs are sequestered in the spleen and the storage life is limited to about 2 weeks.
Like gene therapy vectors, cells may deliver therapeutics, but there is also a need for drug delivery systems for cell and gene therapies.
Various methods of delivery of cells for therapeutic purposes are listed in Table 9 .
An important objective in cell therapy for regenerative medi-cine is delivery of materials to promote growth of cells. One chap-ter in this book describes the development of a self-assembling peptide hydrogel and its potential use as a cell and growth factor delivery vehicle to the infarcted heart in a rodent model of myocar-dial infarction [ 23 ].
3.8.3 Drug Delivery Systems for Cell Therapy
Table 9
Methods of delivery of cells for therapeutic purposes
Injection
Subcutaneous Intramuscular Intravenous Intrathecal
Implantation into various organs by surgical procedures, e.g., brain, spinal cord, myocardium
Oral intake of encapsulated cells Pharmacologically active microcarriers Use of special devices for delivery of cells
Cell delivery systems to promote growth of cells for regenerative medicine © Jain PharmaBiotech
The properties of an ideal macromolecular drug delivery or biomedical vector are:
● Structural control over size and shape of drug or imaging- agent cargo space
● Biocompatible, nontoxic polymer/pendant functionality
● Precise, nanoscale container and/or scaffolding properties with high drug or imaging-agent capacity features
● Well-defi ned scaffolding and/or surface modifi able functional-ity for cell-specifi c targeting moieties
● Lack of immunogenicity
● Appropriate cellular adhesion, endocytosis, and intracellular traffi cking to allow therapeutic delivery or imaging in the cyto-plasm or nucleus
● Acceptable bio-elimination or biodegradation
● Controlled or triggerable drug release
● Molecular level isolation and protection of the drug against inactivation during transit to target cells
● Minimal nonspecifi c cellular and blood-protein binding properties
● Ease of consistent, reproducible, clinical-grade synthesis Oral route remains the most common method of drug delivery.
Efforts are constantly made to made this route more effi cient and faster.
Fast-disintegration technology is used for manufacturing these tablets. The advantages of fast-dissolving tablets are:
● Convenient to take without the use of water
● Easier to take by patients who cannot swallow
● Rapid onset of action due to faster absorption
● Less gastric upset because the drug is dissolved before it reaches the stomach
● Improved patient compliance
Capsules and other protective coatings have been used to protect the drugs in their passage through the upper gastrointestinal tract for delayed absorption. The coatings also serve to reduce stomach irri-tation. The softgel delivers drugs in solution and yet offers advan-tages of solid dosage form. Softgel capsules are particularly suited for hydrophobic drugs which have poor bioavailability because these drugs do not dissolve readily in water and gastrointestinal juices. If hydrophobic drugs are compounded in solid dosage forms, the dissolution rate may be slow, absorption is variable, and the 3.9 Ideal Properties
of Material for Drug Delivery
3.10 Innovations for