Search

In recent years, the rapid growth and availability of protein and peptide therapeutics has not only expanded the boundaries of modern science but has also revolutionized the practice of medicine today. The potential of such therapies, however, is greatly limited by the innate instabilities of proteins and peptides, which is further magnified during therapeutic formulation processing, transport, storage, and administration. In this paper, we will consider the unique stability challenges associated with protein/peptide polymeric delivery systems from an engineering approach oriented towards the quantification and modification of amino acid-based cargo stability. While a number of methods have been developed for the purposes of quantifying factors affecting protein and peptide stability, current measurement techniques remain largely limited in scope in regard to polymeric drug delivery systems. This paper will primarily describe the influence of water content, pH, and temperature on protein and peptide stability within polymer-based delivery systems. Moreover, we will review current instrumentation used to quantify factors affecting protein/peptide stability with respect to water content, pH, and temperature. Lastly, we will outline several recommendations to help guide future research efforts to develop methods more specific to quantifying protein/peptide stability within polymer-based delivery systems.

Graphical abstract, Engineering vaccine-based therapeutics for infectious diseases is highly challenging, as trial formulations are often found to be nonspecific, ineffective, thermally or hydrolytically unstable, and/or toxic. Vaccines have greatly improved the therapeutic landscape for treating infectious diseases and have significantly reduced the threat by therapeutic and preventative approaches. Furthermore, the advent of recombinant technologies has greatly facilitated growth within the vaccine realm by mitigating risks such as virulence reversion despite making the production processes more cumbersome. In addition, seroconversion can also be enhanced by recombinant technology through kinetic and nonkinetic approaches, which are discussed herein. Recombinant technologies have greatly improved both amino acid-based vaccines and DNA-based vaccines. A plateau of interest has been reached between 2001 and 2010 for the scientific community with regard to DNA vaccine endeavors. The decrease in interest may likely be attributed to difficulties in improving immunogenic properties associated with DNA vaccines, although there has been research demonstrating improvement and optimization to this end. Despite improvement, to the extent of our knowledge, there are currently no regulatory body-approved DNA vaccines for human use (four vaccines approved for animal use). This article discusses engineering DNA vaccines against infectious diseases while discussing advantages and disadvantages of each, with an emphasis on applications of these DNA vaccines. Statement of Significance This review paper summarizes the state of the engineered/recombinant DNA vaccine field, with a scope entailing “Engineering DNA vaccines against infectious diseases”. We endeavor to emphasize recent advances, recapitulating the current state of the field. In addition to discussing DNA therapeutics that have already been clinically translated, this review also examines current research developments, and the challenges thwarting further progression. Our review covers: recombinant DNA-based subunit vaccines; internalization and processing; enhancing immune protection via adjuvants; manufacturing and engineering DNA; the safety, stability and delivery of DNA vaccines or plasmids; controlling gene expression using plasmid engineering and gene circuits; overcoming immunogenic issues; and commercial successes. We hope that this review will inspire further research in DNA vaccine development.

Intracellular nucleic acid delivery has the potential to treat many genetically-based diseases, however, gene delivery safety and efficacy remains a challenging obstacle. One promising approach is the use of polymers to form polymeric nanoparticles with nucleic acids that have led to exciting advances in non-viral gene delivery. Understanding the successes and failures of gene delivery polymers and structures is the key to engineering optimal polymers for gene delivery in the future. This article discusses the polymer structural features that enable effective intracellular delivery of DNA and RNA, including protection of nucleic acid cargo, cellular uptake, endosomal escape, vector unpacking, and delivery to the intracellular site of activity. The chemical properties that aid in each step of intracellular nucleic acid delivery are described and specific structures of note are highlighted. Understanding the chemical design parameters of polymeric nucleic acid delivery nanoparticles is important to achieving the goal of safe and effective non-viral genetic nanomedicine.

Treatment of age-macular degeneration requires monthly intravitreal injections, which are costly and have serious risks. The objective of this study was to develop a novel intraocular implant for drug delivery. The capsule drug ring is a reservoir inserted in the lens capsule during cataract surgery, refillable and capable of delivering multiple drugs. Avastin® was the drug of interest in this study. Prototypes were manufactured using polymethylmethacrylate sheets as the reservoir material, a semi-permeable membrane for controlled delivery and silicone check valves for refilling. The device showed near zero-order release kinetics and Avastin® stability was investigated with accelerated temperature studies.

Background Thrombus formation on or near the aortic valve has been reported in HeartMate II (Thoratec, Pleasanton, CA) left ventricular assist device (LVAD) patients whose aortic valves do not open. With an akinetic valve, thrombogenesis is more likely. Thrombus formation may lead to neurologic events, placing the patient at greater risk. Aortic valve stenosis and/or regurgitation have also been observed with akinetic aortic valves. Assessing aortic valve opening is crucial when optimizing rotations per minute (rpm) to minimize embolic risk and aortic valve stenosis but presently relies solely on echocardiography, intermittent decreases in rpms to force aortic valve opening, and monitoring of pulse pressure. We hypothesized the electrical current waveforms of the HeartMate II would reveal whether the aortic valve was opening due to pressure changes in the left ventricle to allow for continuous monitoring and control of aortic valve opening ratios. Methods Electrical HeartMate II current waveforms of patients from 2008 to 2009 that were recorded at the time of echocardiograph procedures were analyzed using a modified Karhunen-Loeve transformation with a training set of electrical waveforms from 8,860 HeartMate II electrical current recordings from 2001 to 2009. Results The study included 6 patients. The electrical current magnitude of the projection of the electrical current waveforms onto the training set's eigenvectors was statistically significantly greater in 4 of the 6 patients when the aortic valve was closed, confirmed by echocardiography. The 2 patients who did not have a large increase in the magnitude had mild aortic valve regurgitation. Conclusion Electrical current analysis for rotary non-pulsatile pumps is a means to develop a physiologic feedback algorithm for an auto-mode, which currently does not exist. Constant regulation and optimization of rotary non-pulsatile LVADs would minimize patients' risk for neurologic events and aortic valve stenosis.