Current Pharmaceutical Biotechnology - Volume 4, Issue 5, 2003

Properties and utilities of macromolecules have been studied in various fields for many years. At the publication of this Issue, articles from PubMed alone related to ‘polymer’ only approximated 170,000 for the last 40 years. These macromolecules have primarily been investigated and used in the medical, pharmaceutical and biotechnology fields to modulate drug delivery and provide optimal safety for human applications. This Special Issue focuses on polymers that are currently available for clinical use. Natural polymers can be classified into two categories, plasma components (e.g., proteins and lipoproteins) and plant- or animal-derived polysaccharides. These polymers have been traditionally studied because of their favorable safety profile. Synthetic polymers, such as poly(lactide-co-glycolide) (PLGA) and N-(2-hydroxypropyl) methacrylamide copolymers (HPMA), have been also throroughly studied. PLGA is for instance currently used in commercial products for cancer treatment (leuprolide acetate formulated with PLGA: Lupron Depot(r) (TAP Pharmaceutical Products Inc., IL, USA), Eligard(r) (Atrix Laboratories, Inc., CO, USA)) and HPMA-drug conjugates are being evaluated in clinical trials. Additional synthetic polymers such as ethylene-co-vinylacetate and polyvinylacohol also possess attractive properties that are exploited in drug delivery systems. Other polymers, usually regarded as ‘intelligent polymers’, that respond with large property changes to small physical and chemical stimuli are increasingly being investigated. In addition to their applications as pharmaceutical drug delivery systems, polymers are also intensively explored in tissue engineering and gene therapy. This Special Issue deals comprehensively with various topics such as in vitro and in vivo characteristics, toxicity, current use and future applications of the above-mentioned polymers. The article titled “Safety and Utilization of Blood Components as Therapeutic Delivery Systems” by Dr. Adams et al. discusses various drug delivery systems using blood components such blood cells and lipoproteins. Dr. Mehvar intriguingly reports on drug delivery systems using polysaccharaides with a central focus on dextran and pullulan in the review titled “Recent Trends in the Use of Polysaccharides for Improved Delivery of Therapeutic Agents: Pharmacokinetic and Pharmacodynamic Perspectives”. Dr. Kato et al. summarize the applications of chitin and chitosan derivatives for hospital preparations and drug carriers, and emphasize the usefulness of these compounds in the review titled “Chitin and chitosan derivatives in the pharmaceutical field”. Dr. Rihova et al. provide an update on Phase I data using N-(2-hydroxypropyl) methacrylamide copolymers in the article titled “Clinical Implications of N-(2-Hydroxypropyl)methacrylamide Copolymers”. The article titled “Contribution of Poly(amino acids) to Advances in Pharmaceutical Biotechnology” by Dr. Chiang et al. describes the role for poly(amino acids) in drug delivery systems including their use in ‘hot topics’ such as vaccine and gene delivery. Dr. Shastri describes the applications of non-biodegradable polymers, including marketable products in the medical field, in the review titled “Non-degradable Biocompatible Polymers in Medicine: Past, Present and Future”. The final contribution from Dr. Bromberg describes an overview on intelligent polymers in the review titled “Intelligent Polyelectrolytes and Gels in Oral Drug Delivery”.

In recent years, natural blood components have been extensively studied as the advanced therapeutic delivery systems. The blood components which can potentially be used as the therapeutic delivery systems include different types of cells, such as erythrocytes and lymphocytes, macromolecular complexes such as lipoproteins and antibody or albumin conjugates and other molecules. This review article covers the progress in this topic, specifically, including the safety issues and the utilization of these component. It can be seen through the literature that the blood components as the therapeutic delivery systems have a number of advantages over traditional pharmaceutical products. The efficacy and practice of the applications, however, require significant amount of development work in the near future.

New and innovative methods of delivery of therapeutic agents using polysaccharides have been recently developed, which target site of action, increase the intensity and / or prolong pharmacologic action, and / or reduce toxicity of small molecule drugs, proteins, or enzymes. This review is focused on the role of dextran, pullulan, and mannan polysaccharides in such applications. While dextran and pullulan are glucose polymers with different glucosidic linkages, mannan is composed of mannose units. In terms of pharmacokinetics of the carriers themselves, molecular weight (MW), electric charge, various chemical modifications, and degree of polydispersity and / or branching would mostly determine their fate in vivo. Generally, large MW polysaccharides (MWs ≥ 40 kD) have low clearance and relatively long plasma half life, resulting in accumulation in reticuloendothelial or tumor tissues. The tumor accumulation in most cases is a passive targeting due to “enhanced permeation and retention” of macromolecules by tumors. Additionally, drugs such as anticancer agents may be actively targeted to specific cells by polysaccharides to which appropriate ligands are attached. In terms of mode of use, polysaccharides have been utilized in a variety of innovative ways for improvement of drug delivery. Their most important application has been as carriers for preparation of macromolecular prodrugs that are normally inactive and need to release the active drug at the site(s) of interest. Also, they have been used for preparation of macromolecule-protein conjugates, which may retain the activity of the proteins, in order to increase the duration of effect and decrease the immunogenicity of proteins. Several other new applications, such as polysaccharide-anchored liposomal formulations, have also been gained attention recently and are briefly reviewed here. Finally, four recent examples of polysaccharidebased delivery systems involving specific drugs / imaging agents are reviewed in detail in terms of their development, pharmacokinetics, and pharmacodynamics. Collectively, these data suggest that macromolecular polysaccharides are promising agents for improving drug delivery.

Chitin and chitosan derivatives are used as excipients and drug carriers in the pharmaceutical field. Their derivatization contributed to expansion of application and decrease toxicity. Chitosan is used as an excipient in oral dosage form. Chitosan tablet can exhibit a sustained drug release compared to commercial products. Films prepared using chitin or chitosan have been developed as wound dressings, oral mucoadhesive and water-resisting adhesive by virtue of their release characteristics and adhesion. Intratumoral administration of gadopentetic acid-chitosan complex nanoparticles (approximately 430 nm in diameter) has been more effective for gadolinium neutron-capture therapy compared with a group treated with the solution. Compared to intragastrical feeding with diphtheria toxoid (DT) in PBS, a strong enhancement of the systemic (IgG) and local (IgA) immune responses against DT has been observed in mice fed with DT loaded chitosan microparticles (approximately 4.7 μm in size). When DNA-loaded chitosan microspheres (1.15 - 1.28 μm) were intramuscularly administrated into mice, high ß-galactosidase and luciferase productions were obtained even after a long post-transfection period (12 weeks). N-Succinyl-chitosan (Suc-Chi) has been studied for cancer chemotherapy as a drug carrier and the conjugates of mitomycin C with Suc-Chi exhibited good antitumor activities against various tumors. Furthermore, trimethyl-chitosan and monocarboxymethyl-chitosan has been shown to be effective as intestinal absorption enhancers due to their physiological properties. Chitosan-thioglycolic acid conjugates has been found to be a promising candidate as scaffold material in tissue engineering due to their physicochemical properties. This review summarizes the application of chitin and chitosan derivatives for hospital preparations and drug carriers.

Different anticancer drugs, farmorubicin, doxorubicin, paclitaxel and cis-platin have been conjugated through a Gly-Phe-Leu-Gly tetrapeptide side chain to a water-soluble synthetic polymeric carrier based on N-(2-hydroxypropyl)methacryalmide (HPMA) non-targeted or targeted with galactosamine and / or human IVIg and used in Phase I clinical trials. Conjugation of the drugs to the polymeric carrier that is non-toxic and non-immunogenic in man significantly decreased their non-specific organ toxicities and increased maximum tolerated dose up to 5 times. Macromolecular therapeutics based on HPMA have radically different pharmacokinetics. Drugs are not released from their polymeric carrier and remain in the peripheral blood and urine of patients mostly in their polymer-bound form. A clinical response against some refractory cancers was recorded in Phase I clinical trials. It was also demonstrated that doxorubicin-HPMA copolymer conjugates containing an immunoglobulin moiety have both cytostatic and immunomobilizing activity.

Recently, protein biotechnology generates tremendous impacts in therapeutic products. These products include enzymes, antibodies, hormones, blood factors, growth factors and regulatory factors. Protein, vaccine and gene therapy drugs could be formulated with suitable biomaterials to deliver active agents to their target sites at the right time and maintain therapeutic effects for proper durations. In this review article, we focus on poly(amino acids) or polymerized amino acids for their applications in drug delivery systems, vaccines, and gene therapy. The nomenclatures of poly(amino acids) are briefly introduced to systematically express synthetic polypeptides. In drug delivery systems, we introduce two applications of poly(amino acids) in pharmaceutical biotechnology, either as carriers to facilitate drug delivery, or as biomaterials to be formulated as suitable delivery systems for application in tissue engineering. Many short polypeptides are mapped from antigen motifs and used for vaccination. These poly(amino acids) provide protective effects in animal challenge tests and potential application in vaccine development to be briefly introduced. Finally, some reports related to new developed poly(amino acids) as DNA carriers for achieving gene delivery are also described in the text.

Polymers have a long history in medicine. Their uses to date range from traditional applications such as catheters, syringes, blood contacting extra corporeal devices to matrices for drug delivery, cell encapsulation and tissue regeneration. Polymers can be broadly classified on the basis of the reactivity of their chemical backbone (or susceptibility of the backbone to breakdown upon exposure to water, i.e., hydrolysis) as non-degradable and degradable. In this review, the polymers that exhibit no to very low degradation in aqueous and biological environments will be covered. The applications of various polymers both in traditional and emerging medical areas is discussed in the context of its chemical structure to better enable material selection for biomedical research.

The present review concerns smart, or intelligent polymers for oral administration that change conformation in aqueous solutions in response to external stimuli such as pH or temperature. We concentrate on charged polymers and gels with polyelectrolyte properties. Because of the ionization at a certain pH or in response to changes in the ionic composition of the solution, a polyelectrolyte has better chances of displaying smart properties than a neutral polymer. When such smart polyelectrolyte is cross-linked by covalent or hydrogen bonding and / or physical aggregation or is entangled, it forms an environmentally sensitive gel capable of swelling and collapse in an aqueous medium. Varying pH, temperature, and microbial flora are found in the gastrointestinal tract, and thus pH- sensitive polymers and gels that can be degraded by specific enzymes and / or inhibit proteolytic enzymes can be tailored for the efficient site-specific therapy. Smart polymers wield a lot of promise in the targeted, site-specific administration where they can provide advantages in loading of sensitive drugs such as proteins and peptides, while releasing the drug at a specific pH or in response to the presence of certain microbial flora.