Chemotherapeutic engineering: Application and further development of chemical engineering principles for chemotherapy of cancer and other diseases

This review defines chemotherapeutic engineering as an engineering discipline that applies and further develops chemical engineering principles, techniques and devices for chemotherapy of cancer and other diseases. It provides new challenges as well as new opportunities for chemical engineering. Chemical engineering has substantially changed the human civilization through its services and products to improve the quality of life for human being. It is now time for chemical engineering to contribute to the most important aspect of the quality of life—human health care. Cancer and cardiovascular diseases are the leading causes for deaths. Chemotherapy is one of the most important treatments currently available for cancer and other diseases such as cardiovascular diseases. The present status of chemotherapy is far from being satisfactory. Its efficacy is limited and patients have to suffer from serious side effects, some of which are life-threatening. Chemotherapeutic engineering is emerging to help solving the problems in chemotherapy and to eventually develop an ideal way to conduct chemotherapy with the best efficacy and the least side effects. This review gives, from an engineering point of view, brief introductions to cancer and cancer treatment, chemotherapy and the problems involved in chemotherapy, and the possible roles of chemical engineering in solving the problems involved. Progress in developing various controlled and targeted drug delivery systems is reviewed with an emphasis on nanoparticles of biodegradable polymers and lipid bilayer vesicles (liposomes). Preparation, characterization, in vitro release, cell line experiments and animal testing of drug-loaded polymeric nanoparticles are described with paclitaxel as a prototype drug, which is one of the best anticancer drugs found in nature. A novel drug delivery system, liposomes-in-microspheres, is used as an example for possible combinations of the existing polymer- and lipid-based delivery systems. Research of molecular interactions between the drug and the cell membrane is also reviewed, with the lipid monolayer at the air-water or oil-water interface and bilayer vesicles as models for the cell membrane. Finally, mathematical modeling in chemotherapeutic engineering is discussed with typical examples in the literature. This review is a short introduction of chemotherapeutic engineering to chemical engineers, biomedical engineers, other engineers, clinical oncologists, and pharmaceutical scientists, who are interested in developing new dosage forms of drugs for chemotherapy of cancer and other diseases with the best efficacy and the least side effects.     

Formulating Drug Delivery Systems by Spray Drying

The knowledge of the potential use of the spray-drying technology to prepare microparticulate drug delivery systems—microspheres and microcapsules—has been strongly improved over the last years. Various microparticulate spray drying systems used as vehicles for drug encapsulation and delivery that have been investigated for different purposes are presented here, including spray-dried powders formulated with hydrophilic polymers allowing controlled drug release, biodegradable microspheres prepared from aqueous systems, and spray-dried silica gel microspheres.     

Development of therapeutic contact lenses using a supercritical solvent impregnation method

We present some selected results indicating the feasibility of preparing therapeutic finished ophthalmic articles, namely commercially available soft contact lenses, using a supercritical solvent impregnation (SSI) technique. Several commercial soft contact lenses were tested and, among these, four lenses were selected for more complete studies: Nelfilcon A (FocusDailies^®, CIBA Vision), Omafilcon A (Proclear^® Compatibles, CooperVision), Methafilcon A (Frequency^® 55, CooperVision) and Hilafilcon B (SofLens^® 59 Comfort, Bausch & Lomb). Supercritical carbon dioxide (scCO₂) was the chosen supercritical fluid and two ophthalmic drugs were tested: flurbiprofen (a NSAID, hydrophobic) and timolol maleate (an anti-glaucoma drug, hydrophilic). The effects of operational pressure, of impregnation duration and of the addition of a cosolvent (ethanol) were studied on the overall drug loading yields. Depending on the experiment, we employed pressures from 9 up to 16 MPa and impregnation times from 30 up to 180 min. Temperature was kept constant and equal to 313 K. The employed depressurization rates were kept low and between 0.1 and 0.2 MPa/min.Results are discussed in terms of the employed operational conditions and taking in consideration all the possible interactions between supercritical fluids, drugs, cosolvents and the polymers which compose the employed hydrogel contact lenses. In vitro drug release experiments were carried out in order to evaluate the resulting drug release profiles. Obtained results were also compared with drug-loaded contact lenses obtained by conventional drug “soaking” in aqueous solutions. Results also proved that SSI can be considered as a viable, efficient and safe alternative for the impregnation of drugs, including those of hydrophobic character or presenting low aqueous solubility, into commercial soft contact lenses. SSI proved to be a “tunable” process since the variation of the employed operational conditions indicated that it is possible to control the amount of impregnated drug. In the end, the ophthalmic articles were recovered undamaged and without the presence of harmful solvent residues. This method also permits to process already prepared commercial contact lenses, without interfering with their manufacture methods and, after processing, store them for future use.     

Development of docetaxel-loaded PEG–PLA nanoparticles using surfactant-free method for controlled release studies

Docetaxel (DTX)-loaded poly(ethylene glycol)–poly(D,L-lactide) is prepared by nanoprecipitation method in the absence of any surfactants. The average particle size of the copolymer was found to be 101?nm. The drug entrapment efficiency (%) and drug loading (%) of polymer were found to be 9.471?±?0.047 and 94.71?±?0.466, respectively. The in vitro drug release characteristics show the controlled release of 98% of docetaxel in 72?h. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis measured in terms of cleaved Poly(ADP-ribose) Polymerase (PARP) and cleaved caspase-3 protein expression shows that the copolymer has better cytotoxicity effect and apoptosis in comparison to free DTX in HeLa cells.     

MEMS-Based Controlled Drug Delivery Systems: A Short Review

The use of microelectromechanical systems-based drug delivery vehicles is on the rise. These advancements in the technologies have enabled the researchers in developing miniaturized devices including drug delivery platforms. This has opened up a new arena in pharmaceutical research. The main advantage of these devices is their ability to control the release profile of the drugs in a temporal scale. The main components of the microelectromechanical systems-based drug delivery devices are the microsensors, microvalves, micropumps, microchannel and a miniaturized control system. The current review discusses the different pumping mechanisms and clinical applications of the microelectromechanical systems-based delivery devices.     

Nimesulide adsorbed on silica aerogel using supercritical carbon dioxide

Silica aerogel (SA) was loaded with nimesulide, a drug model compound, to demonstrate the potentiality of adsorption processes based on the usage of supercritical carbon dioxide to treat poorly water-soluble drugs, forming new kinds of drug delivery systems. Adsorption isotherms and kinetics were measured and described by models. The effect of pressure, temperature and solution concentration on loaded SA were also studied. Modelling of kinetic data showed that the sorption process was best described by a pseudo-second-order model. The adsorption isotherm data were best fitted by the Freundlich isotherm. The drug/SA composites were characterized using scanning electron microscopy, X-ray microanalysis, and FT-IR. Release kinetics of the adsorbed drug were also evaluated by in vitro dissolution tests. Results showed that nimesulide can be uniformly dispersed into the aerogel and that the release rate of nimesulide from the composite, constituted by drug and silica aerogel, is much faster than that of the crystalline drug.     

Single-step assembly of polymer-lipid hybrid nanoparticles for mitomycin C delivery

Mitomycin C is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its clinical use is still hindered by the mitomycin C (MMC) delivery systems. In this study, the MMC-loaded polymer-lipid hybrid nanoparticles (NPs) were prepared by a single-step assembly (ACS Nano 2012, 6:4955 to 4965) of MMC-soybean phosphatidyhlcholine (SPC) complex (Mol. Pharmaceutics 2013, 10:90 to 101) and biodegradable polylactic acid (PLA) polymers for intravenous MMC delivery. The advantage of the MMC-SPC complex on the polymer-lipid hybrid NPs was that MMC-SPC was used as a structural element to offer the integrity of the hybrid NPs, served as a drug preparation to increase the effectiveness and safety and control the release of MMC, and acted as an emulsifier to facilitate and stabilize the formation. Compared to the PLA NPs/MMC, the PLA NPs/MMC-SPC showed a significant accumulation of MMC in the nuclei as the action site of MMC. The PLA NPs/MMC-SPC also exhibited a significantly higher anticancer effect compared to the PLA NPs/MMC or free MMC injection in vitro and in vivo. These results suggested that the MMC-loaded polymer-lipid hybrid NPs might be useful and efficient drug delivery systems for widening the therapeutic window of MMC and bringing the clinical use of MMC one step closer to reality.     

Synthesis of polypyrrole nanowire network with high adenosine triphosphate release efficiency

A novel drug release system based on polypyrrole (PPy) nanowire network is developed for controlled adenosine triphosphate (ATP) release. Interestingly, the formation of the PPy nanowire networks is induced by ATP itself, i.e. ATP serves as both the morphology-directing agent and the model drug. More importantly, it should be pointed out that using ATP as morphology-directing agent for the formation of the PPy nanowire network can significantly increase the ATP release efficiency due to the high surface area of the resulting nanowire network. The experiment results show that ATP release efficiency increases from 53% (for conventional cauliflower-like PPy) to 90% (for PPy nanowire network) within 45 h upon electrical stimulation.     

Synthesis of water dispersible reduced graphene oxide via supramolecular complexation with modified β-cyclodextrin

A noncovalent functionalization of the edges of reduced graphene oxide (RGO) with β-cyclodextrin-graft-hyperbranched polyglycerol (β-CD-g-HPG) was successfully performed via a host-guest interaction. The results showed that β-CD-g-HPG disperses the graphene sheets better than pure β-CD or HPG. The resulted supramolecular structure is stable in neutral water medium more than one week. However, in acidic medium the host-guest interaction is collapsed and graphene nanosheets precipitate.     

Preparation of β-Cyclodextrin-Dextran Polymers and their Use as Supramolecular Carrier Systems for Naproxen

Summary Dextran, previously activated by periodate oxidation, was grafted with mono-6-amino-6-deoxy-β-cyclodextrin, mono-6-ethylenediamino-6-deoxy-β-cyclodextrin, and mono-6-butylenediamino-6-deoxy-β-cyclodextrin by reductive alkylation in the presence of NaBH₄. The polymers were able to form inclusion complexes with Naproxen, increasing the solubility of the drug by 2.2-2.6 folds. The β-cyclodextrin-grafted dextrans were used as macromolecular carriers for Naproxen, improving the “in vivo” anti-inflammatory activity of the drug.     

Review on rubbers in medicine: natural,silicone and polyurethane rubbers

Abstract

Natural, silicone and polyurethane rubbers are considered as three important biomaterials which have found widespread applications in medical technology. Biocompatibility, biodurability, sterilisability, processibility, as well as mechanical properties, such as flexibility and resilience, are properties that make these kinds of rubbers appropriate candidates for medical applications. Medical devices based on natural rubber, silicone and polyurethane rubbers include cardiac pacemaker leads, mammary prostheses, artificial skin, catheters, denture liners, diaphragms, blood pressure cuff coil, tubes and seals. These types of rubbers are commonly used in controlled drug delivery systems as a carrier for pharmaceutical agents and in the fabrication of other medical devices. These polymers were evaluated for release of hormones (e.g. estradiol and progesterone), metronidazole, nonoxynol-9, etc. In this paper, some recent advances on the development of these polymers in the biomedical field and some reports on the modification and improvement of their properties such as drug release and mechanical properties are reviewed.     

Impregnation of vitamin E acetate on silica mesoporous phases using supercritical carbon dioxide

Impregnation of a drug model (α-tocopheryl acetate) into mesoporous host matrices has been carried out using supercritical carbon dioxide (SC CO₂) as impregnation solvent at 15 MPa and 313 K with a flow rate of 500 g h⁻¹. The operating conditions were defined following the solute concentration in the fluid phase as a function of pressure and carbon dioxide flow rate. Solubility measurements of α-tocopheryl acetate were first performed at 313 K for pressures ranging 10-20 MPa. High values of solubility in SC CO₂ were measured: 6 wt% at 10 MPa and 14 wt% at 20 MPa. Measurements of the concentration of the solute in SC CO₂ in the experimental conditions of impregnation in dynamic mode showed than it was ten times lower than the solubility. The variations of this concentration have been studied at 313 K, for a pressure varying from 8 to 15 MPa, and for a carbon dioxide flow rate varying from 120 to 600 g h⁻¹. Two different host matrices were used: a commercial chromatographic silica support and a MCM-41-type mesoporous organized silica synthetized at the laboratory. This latter showed the best drug loading of 1.14 g per gram of adsorbent. The drug loadings obtained in supercritical media were similar to the ones obtained in liquid media using hexane as impregnation solvent. Nevertheless, the maximum loading was obtained after 1 h of impregnation in SC media while 4 h were needed in liquid media.     

Protective and retentive effects of liposomes on water-degradable hydrocortisone acetate in dermatological applications

Various dermatological samples containing Liposomes as a drug carrier were prepared, and the effects of variations in the dermatological formulations, such as liposornal encapsulation, base materials, and the purity of lipid products, on drug stability and characteristics for effective topical drug delivery were investigated. Hydrocortisone-21-acetate, a hydrophobic and water-degradable, anti-inflammatory agent, was used as the model drug. It was found that the liposomally encapsulated drug was more stable than the free-form drug in an ointment formulation. Also, the hydrogel base was found to be effective in maintaining drug stability in spite of its high water content. Another evidence that Liposomes were surrounding drug particles in the base was obtained from anin vitro test of drug permeation from liposome-hydrogel through the pig ear skin. The permeability of hydrocortisone acetate through the skin membrane was found to be 2.7-fold lower in the case of liposome-hydrogel than in the case of free-drug hydrogel. The results also suggested that Liposomes play a role in localizing drug molecules in the skin membrane.     

In vitro degradation behavior of biodegradable 4-star micelles

Drug delivery vectors for sustained release include a variety of polymeric constituents, both natural and synthetic. Among synthetic polymers several linear block copolymer systems have been explored for use as drug delivery vectors. Release of the pharmaceutical agent is affected by the degradation characteristics and/or by the swelling of the polymer. The goal of this study is to evaluate the degradation behavior of branched polyethylene oxide polylactide polyether ester as a drug delivery vector. Three samples of a star polyethylene oxide/polylactide copolymer with differing polylactide chain lengths were evaluated by characterizing the thermal properties of the neat polymer and in vitro degradation behavior.The thermal and morphological properties were examined by DSC, TGA and XRD. The in vitro polymeric micelle samples were observed over time by UV-vis, TEM and fluorescence. The four star PEO-PLA polymers have exceptional amphiphilic characteristics, which enable their use for a variety of applications. The polymers are thermally stable at biological conditions. In addition, the star polymers have shorter degradation times as compared to previously reported linear PLA and PEG-PLA copolymers, suggesting use as a short-term drug release agent. The four star PEO/PLA copolymer may be an excellent candidate for drug delivery applications.     

Drug release kinetics from monolayer films of glucose-sensitive microgel

To study the drug release behaviors of glucose-sensitive poly(N-isopropylacrylamide-co-3-acrylamidophenylboronic acid) (P(NIPAM-PBA)) microgels, P(NIPAM-PBA) microgel monolayers were prepared by the modification of poly(N-isopropylacrylamide-co-acrylic acid) microgel monolayers with 3-aminophenylboronic acid under EDC catalysis. Alizarin Red S (ARS) and FITC-labeled insulin (FITC-insulin) were loaded in the monolayers respectively. Their release kinetics under various conditions were measured. For both drugs, at low temperature, the drug release can be described as passive diffusion of the drugs. At temperature higher than the phase transition temperature, however, the drugs are released via a “squeeze-out” mechanism. Glucose-regulated release for both drugs was observed. At all temperatures glucose enhances the release of ARS because it competes with ARS for binding with PBA groups. For FITC-insulin, glucose enhances its release at 4 °C, but retards at 37 °C. These results will guide the design of self-regulated insulin release systems based on P(NIPAM-PBA) microgels.     

Engineering oligo(ethylene glycol)-based thermosensitive microgels for drug delivery applications

Novel oligo(ethylene glycol)-based thermosensitive microgels with well engineered core-shell structures were developed for storage and delivery of chemotherapeutic agents. The core is consisted of hydrophobic poly[2-(2-methoxyethoxy)ethyl methacrylate], while the shell is consisted of hydrophilic copolymer of 2-(2-methoxyethoxy)ethyl methacrylate with oligo(ethylene glycol) methyl ether methacrylates. These core-shell microgels exhibit tunable volume phase transition temperature and excellent colloidal stability across the physiologically important temperature range. The thickness of the hydrophilic shell can control the collapsing degree (or mesh size) of the hydrophobic core network, which can be utilized to significantly increase the loading capacity of the model hydrophobic drugs dipyridamole by tailoring the shell thickness of microgels. While the microgels are nontoxic, the drug molecules released from the microgels remain active to kill the cancer cells. The presented results provide important guidelines for the rational design of core-shell structured polymeric microgels for drug uptake and release applications.