Researchers from UC San Diego have invented a new form of materials, polymer-integrated crystals (PIX), which combine the structural order of protein crystals with the dynamic, stimuli-responsive properties of synthetic polymers. The inventors have shown that the crystallinity, flexibility, and chemical tunability of PIX can be exploited to encapsulate guest proteins with high loading efficiencies. And, the electrostatic host-guest interactions enable reversible, pH-controlled uptake/release of guest proteins as well as the mutual stabilization of the host and the guest, thus creating a uniquely synergistic platform toward the development of functional biomaterials and the controlled delivery of biological macromolecules.

A major bottleneck in nanocarrier and macromolecule development for therapeutic delivery is our limited understanding of the processes involved in their uptake into target cells. This includes their active interactions with membrane transporters that co-ordinate cellular uptake and processing. Current strategies to elucidate the mechanism of uptake, such as painstaking manipulation of individual effectors with pharmacological inhibitors or specific genetic knockdowns, are limited in scope and biased towards previously studied pathways or the intuition of the investigators. Furthermore, each of these approaches present significant off-target effects, clouding the outcomes. Methods for intracellular transport of nucleic acids are much sought after in the context of both in vitro delivery reagents and in vivo therapeutics. Recently, we found that micellar assemblies of hundreds of amphiphiles consisting of single-stranded DNA which has been covalently linked to a hydrophobic polymer, referred to as DNA-polymer amphiphile nanoparticles or DPANPs, can readily access the cytosol of cells where they modulate mRNA expression of target genomes without transfection or other helper reagents, making them potential therapeutic nucleic acid carriers. However, despite their effective uptake properties and efficacy in the cytosol, it was unknown how these polyanionic structures can enter cells. Indeed, generally, bottlenecks in understanding and achieving delivery and uptake remain a forefront issue in translatability of macromolecular and nanomaterials-based therapeutics generally, including with respect to nucleic acid therapies. The nature of pooled screening requires amplifying a single ~200nt region per cell, leading to screens that require amplification from tens-to hundreds of micrograms of genomic DNA. Inhibitory effects of high DNA concentration per PCR have led to a variety of solutions, ranging from simply pooling hundreds of PCR reactions to utilizing restriction enzyme sites present in the lentiviral backbone constant regions flanking the sgRNA to perform DNA gel electrophoresis and size selection to remove undesired gDNA. However, these approaches can be both expensive and have significant handling challenges when scaled to large screens.

Bioorthogonal ligations encompass coupling chemistries that have considerable utility in living systems. Among the numerous bioorthogonal chemistries described to date, cycloaddition reactions between tetrazines and strained dienophiles are widely used in proteome, lipid, and glycan labeling due to their extremely rapid kinetics. In addition, a variety of functional groups can be released after the cycloaddition reaction, and drug delivery triggered by in vivo tetrazine ligation is in human phase I clinical trials. While applications of tetrazine ligations are growing in academia and industry, it has so far not been possible to control this chemistry to achieve the high degrees of spatial and temporal precision necessary for modifying mammalian cells with single-cell resolution.

Heart failure (HF) is a disease of epidemic portions in the United States affecting over 6 million patients with heart failure in the US, with 400,000 new cases per year. It is the most common cause of non-elective admission to the hospital in subjects 65 yrs and older. The introduction of new drugs over the last 30 years that target pathways critical to progression of HF, along with implantable cardiac defibrillators and resynchronization devices have shown some successes, however, both the morbidity and mortality associated with heart failure remains at unacceptable levels, with as many as 30-40% of affected individuals dying within 5 years of diagnosis. Recently, preclinical and clinical trials have tested gene transfer to increase left ventricular (LV) function, especially in heart failure with reduced ejection fraction.

The National Center for Advancing Translational Sciences and Genetic and Rare Diseases Information Center characterizes Pigmented villonodular synovitis (PVNS) as a rare disease estimated to occur in ~ 5-6 people out of 100,000. This locally invasive tumor most often occurs in younger adults and causes severe damage to joints. The first line of treatment is surgery but at least 50% of patients require multiple surgeries over many years due to re-growth of the tumor.

Many diseases of the central nervous system (CNS) arise from the accumulation of proteins such as α-synuclein (aSyn) in Parkinson’s Disease (PD) or Aß in Alzheimer’s disease (AD). The ability to regulate the expression at the gene transcription level would be beneficial for reducing the accumulation of these proteins or regulating expression levels of other genes in the CNS. aSyn also accumulates in other neurodegenerative diseases including dementia with Lewy Body (DLB), multiple system atrophy (MSA) and Gaucher’s disease. This means that regulation of aSyn expression may be crucial to the therapeutic control of numerous neurodegenerative diseases.

Advances in science are driven by new discoveries which can pave the way to new create new research directions. For example, crystals by the nature of their order in three-dimensional space, cannot flex or expand, but with the integration of macromolecular ferritin crystals with hydrogel polymers can change their dimensions.

Microbial ecologists are increasingly turning to small, synthesized ecosystems as a reductionist tool to probe the complexity of native microbiomes. Concurrently, synthetic biologists have gone from single-cell gene circuits to controlling whole populations using intercellular signaling. 

Neuropathic pain is a type of persistent pain usually occurring longer than 3 months, associated with peripheral nerve problems, but also can arise from chronic inflammatory diseases like arthritis, chemotherapeutic-induced peripheral neuropathy in the treatment of cancer or a neurodegenerative disease or condition. The chronic pain has an extraordinary negative impact on quality of life. While opiates, NSAIDs, and anticonvulsants can relieve pain for short intervals, they are less effective for chronic therapy, particularly when components of the pain state involve persistent inflammation and/or injury to the peripheral nerve. Aside from efficacy, many of the potent agents are beset with limiting side effects and issues related to dependence and addiction. This relative lack of long-term efficacy of even approved agents is evident from clinical trial results, which often indicate that most subjects complete even successful trials with pain that is sufficiently severe as to permit reentry into the same trial. What is needed is a new treatment modality.

The use of traditional probiotic microorganisms to provide therapeutic function for the gut microbiome has a number of limitations. Probiotic bacteria do not colonize the gut because they can’t compete with the resident flora that have evolved for that environment. Current probiotics are a single strain which when used in multiple hosts have not had great success in broad populations and are therefore unpredictable. To alleviate the above problem, a new approach is necessary to colonize the human gastrointestinal tract with greater reliability and for therapeutic value to the patient. 

Gene delivery systems for in vivo therapeutics remain a challenge due to low efficiency or cytotoxicity. Celllular endocytosis is the primary uptake pathway of most nanoplatforms, which results in lysosomal degradation of genetic material and low therapeutic efficacy.

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Brief description not available

As of 2012, the pharmaceutical market share of peptide/protein therapeutics was >$40 billion annually. However, due to their instability in vivo, most peptide therapeutics must be directly injected at the site of action. This has a negative impact on patient compliance and, as such, many peptide therapies are only used clinically as salvage treatments.Several existing approaches for producing peptides protected from proteolysis involve chemical modification of the amino acid sequence. This generally necessitates multiple rounds of structure-function studies to verify that the activity of the peptide is not altered. Other approaches not using chemical modification of the amino acid sequence may involve conjugation of the peptide to a pre-formed higher molecular weight structure, such as a polymer or nanomaterial. The downside of these approaches is that they require multiple conjugation and purification steps and the generation of the high molecular weight carrier. Inefficiencies in cellular uptake and rapid digestion by proteases are two key problems that have limited the clinical efficacy of peptide-based therapeutics.

Macromolecular peptide, protein and oligonucleotide therapeutics have great potential to treat human disease; however, due to their size, they have no ability to enter cells. Peptide/Protein transduction domains (PTDs), also called cell-penetrating peptides (CPPs), promote uptake of macromolecules via endosomal macropinocytosis. However, overcoming the rate-limiting step of endosomal escape remains the major challenge.

A major challenge facing nanoparticle-based drug delivery vehicles with chemotherapy payloads is accumulation in healthy tissue through passive extravasation as well as active uptake by the reticulo-endothelial system. These healthy tissues get a dose of the active drug once the nanoparticles begin to break down resulting in dose limiting side effects. New approaches and platforms are needed to address this issue.

The concept of restricting toxic chemotherapeutics to tumor tissue is not new. In a contemporary version of the approach, a nontoxic, inactive caged drug is selectively delivered to a tumor and low dose radiation is delivered to convert prodrug to active, toxic drug. In 2008, UC inventors attempted to improve on the approach by using nanoparticles. However, technical limitations severely compromised absorption of the excitation radiation and radiation was also quenched by tissue oxygen. Both of these problems have been solved by developing unique compositions, which pave the way for finely localized delivery of therapeutics, in terms of anatomy and timing, that might otherwise be “undruggable”. Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";}

Oxidative stress is caused predominantly by accumulation of hydrogen peroxide and distinguishes inflamed tissue from healthy tissue. Hydrogen peroxide could potentially be useful as a stimulus for targeted drug delivery to diseased tissue. However, current polymeric systems are not sensitive to biologically relevant concentrations of H2O2.

Nucleic acids have exceptional potential in the preparation of complex nanostructured materials for use as therapeutic agents and as powerful investigative tools. However, unmodified nucleic acids are inherently susceptible to enzymatic degradation in biological milieu, limiting their practical utility in detection and as therapeutics in real world applications. Specifically, new strategies are needed for the preparation of well-defined, stable and competent nucleic acid-based materials.

Clinical trials have shown that oncolytic viruses can be systemically delivered safely with limited toxicity; however, several limitations are reached in terms of efficacy. Adenoviruses are commonly used in gene therapy for cancer and are predominantly derived from adenovirus serotype 5 (Ad5), due to their ability to infect a broad range of cells. Although local, intratumoral administration of Ad have produced marked antitumor effects in cancer gene therapy, additional work is required to develop an Ad vector system for systemic administration that can be used to treat both primary and metastatic tumors. Several drawbacks are attributed to rapid clearance of the virus from circulation before they reach their target site. Clearance from the bloodstream is mediated through neutralizing antibodies, inflammatory responses, as well as nonspecific uptake by other tissues such as the lung, liver, spleen, and suboptimal viral escape from the vascular compartment. A range of methods have been designed to overcome these limitations. In general, encapsulation of the virus with a cationic liposome or coating the viral capsid with a cationic polymer has been employed.

Oncolytic viruses can selectively replicate in and kill tumor cells. Over the last two decades significant advances have been made in the preclinical and clinical development of viral based therapy as a platform for the treatment of cancer. Much progress has since been made in understanding viral lifecycles and biology, but their delivery and clearance characteristics remain a major stumbling block for effective therapy. It is believed that the ability to effectively deliver therapeutic viruses systemically would leverage the existing knowledge base on viruses and expand the efficacy of the oncolytic viral platform to patients with disseminated disease.

Dorso-ventral spinal cord pulsation often increases the risk of spinal injections because it leads to a likelihood of local tissue injury and bleeding. Further, delivery of agents into a pulsating spinal cord may result in less than optimal quantities of dug being delivered. Therefore, there is an unmet need for a safer and more efficient method to perform spinal injections.

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Brief description not available

Much recent attention has been given to self-propelled chemically-powered catalytic nanomotors. Among these, catalytic microtube engines are particularly attractive for practical applications due to their efficient bubble-induced propulsion in relevant biological fluids and salt-rich environments. Such powerful microengines are commonly prepared by top-down photolithography, e-beam evaporation, and stress-assisted rolling of functional nanomembranes on polymers into conical microtubes. While offering attractive performance, these methods’ practical utility is greatly hindered by their complexity and related (clean-room) costs. Another approach involves sequential electrodeposition of platinum and gold layers onto an etched silver wire template but offers low yield and inferior propulsion behavior.