Matrix Mediated Viral Gene Delivery: A Review - Bioconjugate

Review Cite This: Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Matrix Mediated Viral Gene Delivery: A Review Douglas Steinhauff†,‡ and Hamidreza Ghandehari*,†,‡,§ Department of Biomedical Engineering and §Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 36 South Wasatch Drive, Salt Lake City, Utah 84112, United States ‡ Utah Center for Nanomedicine, Nano Institute of Utah, 36 South Wasatch Drive, Salt Lake City, Utah 84112, United States

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ABSTRACT: Polymeric matrices inherently protect viral vectors from preexisting immune conditions, limit dissemination to off-target sites, and can sustain vector release. Advancing methodologies in development of particulate based vehicles have led to improved encapsulation of viral vectors. Polymeric delivery systems have contributed to increasing cellular transduction, responsive release mechanisms, cellular infiltration, and cellular signaling. Synthetic polymers are easily customizable, and are capable of balancing matrix retention with cellular infiltration. Natural polymers contain inherent biorecognizable motifs adding therapeutic efficacy to the incorporated viral vector. Recombinant polymers use highly conserved motifs to carefully engineer matrices, allowing for precise design including elements of vector retention and responsive release mechanisms. Composite polymer systems provide opportunities to create matrices with unique properties. Carefully designed matrices can control spatiotemporal release patterns that synergize with approaches in regenerative medicine and antitumor therapies.

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INTRODUCTION Delivery of biological therapeutics can result in altered cellular function and improved pathophysiology. Protein delivery often results in low and short temporal responses insufficient for effective treatment. Gene delivery can provide sustained therapeutic responses to correct existing abnormalities or provide new cellular functions in vivo through viral or nonviral methods. The total number of clinical trials for gene therapeutics is nearing 2600 worldwide, with 132 trials occurring in 2017 alone.1 Applications include, but are not limited to, treatment of cancers and infectious, cardiovascular, and neurological diseases, with more expected to soon achieve clinical approval.1−5 While nonviral approaches are relatively nonimmunogenic, they suffer from poor transfection efficiencies and short transgene expressions. Viral vectors exhibit high transduction efficiencies and potential for long-term transgene expression, but are plagued by patient immunity, dissemination to nontarget sites, and toxicities. Viral delivery can be local or systemic and, depending on the vector, can persist for the duration of vector presence or can be inserted into host genome leading to permanent effects. Preclinical studies have failed to predict the extent of innate, humoral, and T-cell immune responses toward viral vectors6,7 leading to challenges in clinical translation. Intravenous administration can result in transient liver toxicity, off target effects, and inflammatory responses. Despite these challenges, viral vectors have still made it to the market with recent approvals for treatment of head and neck cancer, lipoprotein lipase deficiency, and melanoma.8−11 Polymeric matrix mediated (MM) delivery of viral vectors has been investigated since the 1990s for controlled release, improved localization at target sites, immune shielding, and reduction of other toxicities.12−17 © XXXX American Chemical Society

These benefits have led to the formulations entering clinical trials, showing safety and efficacy for treatment of nonhealing diabetic foot ulcers and vaccination against prostate cancer.18−21 Applications of regenerative medicine and antitumor therapies, can further benefit from carefully designed MM delivery. Regenerative medicine can benefit from MM delivery through increased transduction of target cells and benefits of inherent properties exhibited by matrices. Antitumor therapies utilizing matrices can help ensure an immune balance toward an antitumor response rather than an antiviral response.22 Temporal release patterns are critical parameters affecting therapeutic outcome and can be tuned using polymeric matrices. This review will focus on the additional benefits provided by polymeric matrices for viral gene delivery and how synergy between matrices and viral gene therapies can achieve enhanced outcomes.

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VIRAL VECTORS

Various viral vectors have been investigated in clinical and preclinical stages, providing a range of transgene expression profiles, genetic payload, tropism, inflammatory potential, and physiochemical properties (Table 1). Physiochemical properties of vectors such as size, shape, and surface properties influence their interactions with polymeric matrices. In the Special Issue: Delivery of Proteins and Nucleic Acids: Achievements and Challenges Received: November 26, 2018 Revised: December 20, 2018

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DOI: 10.1021/acs.bioconjchem.8b00853 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Glycoprotein, Large protein, Phosphoprotein, Matrix Protein, Nucleoprotein 320−380 × 260−340 × 240−290 nm30−34 30−60 × 250−300 nm35−37 Dividing/ Nondividing Cells

Vaccinia virus

Baculovirus

Long/Short

no known limit

Yes

Ellipsoidal/barrel/ brick29 Rod-shaped35−37 Yes 25 kb Dividing Cells

Adeno-associated vectors Herpes Simplex Vectors Lentivectors

Short

Diameter: 166 nm28 8 kb Long

Yes

Icosahedral 30−40 kb Short

Yes

Spherical/Ovoid

23

Diameter: 110−200 nm

Negative Diameter: 20 nm No 5 kb27 Long

Icosahedral

MATRIX-MEDIATED DELIVERY OF VIRAL GENE VECTORS In the modern sense, the use of biomaterials for delivery of therapeutic agents began in the 1960s evolving from macroscopic drug delivery systems toward nanoscopic designs capable of delivering fragile cargo such as proteins and genetic vectors.38 Spatiotemporal release of therapeutics can be achieved using synthetic, natural, and recombinant polymers. Synthetic polymers offer a wide range of properties and can be tuned for functionality and degradability, depending on the synthetic methodology and the resulting monomer sequence, molecular weight, and polydispersity. Naturally derived polymer properties will depend on extraction method and source. These polymers must be carefully processed to remove immunogenic components and may contain inherent recognition motifs for cells or enzymes. Recombinant polymers are designed genetically and are created utilizing cellular machinery. This method allows precise control over polymer structure, motif incorporation, and molecular weight.39−42 These three polymer types are reviewed elsewhere.43−45 This review will encompass polymers that have been specifically used in matrix-mediated viral gene delivery through the formation of gel and particulate structures. Gel systems, in this context, are considered to be hydrogels and scaffolds and are largely used for regenerative medicine and localized delivery. Hydrogels are three-dimensional polymeric matrices, which hydrate upon submersion in aqueous solvents swelling to water contents of 70−99%.46 This hydrated state provides delicate packaging of fragile cargo such as viral vectors. Scaffolds support cellular differentiation and proliferation. Some matrices can be hydrogels and scaffolds depending on hydration and ability to regenerate tissues. The particulate systems covered in this review consist of microspheres and microgels, which provide improved viral stability in vivo and sustained release. They largely rely on the physical entanglement of viral vectors within the matrix and are advantageous for systemic treatments. Several polymer structures discussed in this review can be found in Figure 1. Particulate Systems. Particulate systems can be administered locally or systemically presenting an advantageous option to treat widespread disease such as metastatic cancers. Microencapsulation can result in sustained release of viral vectors, increasing stability, and shielding from neutralizing antibodies.12,15,47−50 Past methodologies for particulate synthesis relied upon harsh conditions for encapsulation, and subsequent loss of virus activity. Recently new methods have been developed making microencapsulation of viral vectors more attractive. A list of particulate systems discussed in this article can be found in Table 2. Poly(lactic-co-glycolic acid) (PLGA) copolymers (Figure 1) are widely used biocompatible systems with a wide variety of molecular weights and copolymer ratios available commercially. These polymers degrade upon hydrolysis. Methods to synthesize PLGA microspheres include the use of organic solvents, and their degradation products provide an acidic environment which may deactivate viral vectors resulting in needs for gentler encapsulation methods.51 Microencapsulation of PEGylated

Negative

Gag, Env Hexon, penton, fiber26 Negative Diameter: 80−120 nm Diameter: 70−100 nm25

Yes No

Dividing Cells Dividing/ Nondividing Cells Dividing/ Nondividing Cells Dividing/ Nondividing Cells Nondividing cells Retrovectors Adenovectors

Long Short

8 kb 8 kb

Spherical/Ovoid Icosahedral

23

Dimensions Geometry Enveloped Payload

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Tropism Retargeting

Transgene expression

choice of viral vector to be encapsulated in a biomaterial matrix, factors such as vector geometry (spherical, icosahedral, long vs short axial ratios), size, enveloped vs nonenveloped, major and minor capsid proteins, along with the desired duration of transgene expression need to be considered.

Virus

Table 1. Various Viral Vectors Used in Gene Therapy and Respective Physiochemical Properties

24

Surface Charge

Major Capsid Proteins

Bioconjugate Chemistry

B


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Figure 1. Several polymer systems discussed in this review. Fibrin schematic adapted from McDowall 2006.196

junction size, alterations in molecular weight (MW), and crosslinking with hydrolytically susceptible cross-linkers.60−64 These polymers have been extensively investigated in tissue engineering and drug delivery.58 The use of calcium-ethylenediaminetetraacetic acid (EDTA) as a cross-linker resulted in drastically decreased LV activity due to a drop in pH upon calciumEDTA disassociation and subsequent LV vector instability.55,65 Microgels cross-linked with calcium chloride and calcium carbonate/glucono δ-lactone did not result in reduced LV activity and achieved 60% cumulative release by day 10, despite the drastically smaller mesh sizes compared to LV size (Tables 1 and 2). This is possibly attributed to an increased matrix surface area and an unideal mesh network consisting of closed polymer loops, dangling ends, and slipping chain entanglements.55,66 On-chip polymer blending, a novel microfluidic method to create composite microgels, was employed to optimize material properties and therapeutic potential of encapsulated LV encoding vascular endothelial growth factor (VEGF). Blending provided variation in mechanical properties, degradability, and controllable release kinetics sustained over 10 days. The LV-VEGF microgels produced a marked increase in proangiogenic response compared to controls in a chick chorioallantoic membrane (CAM) assay, resulting from controlled delivery of vectors and limited dissemination to somatic tissues often observed by naked vectors.56,67 This methodological synthesis provides the capability to create composite microgel systems in a controlled manner with tunable functionality. Microfluidic encapsulation results in an alternative methodology for successful incorporation of vectors, with the ability to discretely control volumes and polymer composition for carefully tuned properties. The use of particulate systems for encapsulation of viral vectors has long lagged behind the use of larger structures. While these systems were the first developed, the methodologies of encapsulation resulted in poor yields and/or poor activity of vectors. The recent developments have resulted in methods that can maintain vector activity and providing a level of control that has been long obtainable with macroscopic systems. Gel Structures. Larger gel structures have long been studied for the encapsulation and controlled release of viral vectors. These systems are largely composed of polymers consisting of synthetic, natural, and recombinant polymers. These structures have been used for local delivery of vectors

adenoviruses (ADs) modified with poly(ethylene glycol) (PEG) (Figure 1) resulted in increased physical stability compared to naked vectors in a double emulsion technique. PEGylated ADs exhibited a decreased burst release in comparison to ADs, before following a similar release profile due to PEG−PLGA entanglement resulting in sustained release of 10 days in vitro.48 PLGA microparticles encapsulating ADs exhibited increased infectivity when synthesized using total recirculation one-machine system apparatus (TROMS) compared to traditional emulsion preparation techniques, ameliorating the need for aggressive homogenization that may deactivate viral vectors. Intramuscular administration of PLGA formulations prepared by TROMS in immunocompetent mice showed sustained expression of β-galactosidase for at least 7 weeks. This sustained expression was attributed to immune shielding of encapsulated vectors and increased stability within microparticles.50 Encapsulation of ADs encoding for tissue inhibitors of metalloproteinase into polyDL-lactide-poly(ethylene glycol) microspheres led to encapsulation efficiencies of 60%, posing as plausible candidates for treatment of hepatocellular carcinoma due to large blood filtration of the liver and ability to minimize tumor cell migration and invasion.52,53 The transduction efficiency of HepG2 cells was enhanced by 90%; however, this may be due to the replication-competent nature of the vectors used.54 These microencapsulation methodologies provide gentler conditions for viral vectors resulting in a greater infectivity compared to previous techniques. TROMS reduces the use of high forces that deactivate vectors. The inclusion of PEG domains in multiple synthetic techniques, whether on the viral capsids or the polymeric vehicle, aids in stabilization of the vector capsids leading to improved activity of vectors. Further developments in microencapsulation technologies have resulted from droplet microfluidic technologies with the ability to form micrometer-sized hydrogels with discrete volumes.57 These have been used for lentivirus (LV) encapsulation within alginate microgels (Table 2).55 Alginate is extracted from brown algae and consists of L-guluronate (G) and D-mannonate (M) to form block copolymers.58 The Gblocks can be cross-linked with divalent cations to form intermolecular cross-linking, with cross-linking mechanics relying on molecular weight, G-block length, and M/G ratio.59 Alginates do not support cellular infiltration and can be tuned for precise degradation by mismatched cross-linking C


Alginate (AF350/ AF555)

Poly-DL-lactide-poly (ethylene glycol) Alginate (Low MW)

Poly(lactic-co-glycolic acid)

Parent Material

2% Microgel (50/50 degradable/nondegradable blend) 2% Microgel degradable

2% Microgel nondegradable

2% Microgel AF555

1.5% Microgel (50/50 blend)

Calcium carbonate and glucono delta-lactone (CaCO3-GDL) (wt %) Ethylenediaminetetraacetic acid chelated calcium (CaEDTA-AcOH) (wt%) Calcium chloride (CaCl2) (wt%) 1% Microgel AF350

PEGylated AD

Variations in Structure

Microgel Microgel Microgel

Microfluidics Microfluidics On-chip polymer blending On-chip polymer blending On-chip polymer blending On-chip polymer blending On-chip polymer blending On-chip polymer blending Microgel

Microgel

Microgel

Microgel

Microgel

Microgel

Modified double emulsion Microfluidics

Microspheres

Microspheres Microspheres

Double Emulsion TROMS

Structure Microspheres

Double Emulsion

Fabrication Method

Table 2. Particulate Matrix Systems Used to Encapsulate Viral Vectors Shape

Spherical

Spherical

Spherical

Spherical

Spherical

Spherical Spherical

Spherical

Spherical

Spherical

Spherical

Spherical

Particle Size (μm)

0.104 (1%) - 0.0985 (2%)

0.152 (1%) - 0.158 (2%)

0.126 (1%) - 0.127 (2%)

1.250−3.320

9.43 8.4−10.2

9.3

22

33

82

22

24

2.1 (2% - 3.4 (1%) 35

9.9 (2%) −18 (1%)

2.9 (2%) - 4.8 (1%)

Mesh Size (nm)

Cargo

LV-VEGF

LV-VEGF

LV-VEGF

LV-VEGF

LV-VEGF

LV-GFP LV-VEGF

LV-GFP

AD-GFP AD-βgalactosidase AD-TIMP

AD-GFP

Application

CAM Assay

CAM Assay

CAM Assay

CAM Assay

CAM Assay

Discontinued due to inactivity HEK-293T CAM Assay

HeLa Cells Intramuscular Administration Hepatocellular Carcinoma HEK-293T

HeLa Cells

refs

56

56

56

56

56

55 56

55

55

52,54

48 50

48

Bioconjugate Chemistry Review

D


Gel

Microsphere; Scaffold

Hydrogel; Scaffold Hydrogel; Microgel; Microspheres Hydrogel; Fiber; Nanogel Scaffold Scaffold

Tetronic

Poly(lactic-co-glycolic acid)

Fibrin

E

Elastinlike polypeptides/ Poly (ϵ-caprolactone) Poly (ϵ-caprolactone)

Chitosan/Collagen

Collagen

Polyester ether urethane urea

Polyester urethane urea

Poly-DL-lactide-poly(ethylene glycol) Gelatin

Silk Fibroin Poly-Lactide

Silk-Elastinlike Protein Polymers

Core Shell Fibers

Fibers

Scaffold Composite Blending

Combinatorial delivery

Mechanical Properties

All in one tumor vaccine

AD

AAV

AD

LV, AD

AAV

AAV

oAD, LV

Matrix shaping

Hydrogel; Scaffold Solid fibers; Core shell fibers Solid fibers; Core shell fibers Sponge; Gel

AD AAV, AD

AD, GLV-1h68, oAD

rAAV

Enhanced retention One-step fabrication; Mechanical properties

MMP/Inflammation responsive

LV, rAAV, AD

AD, rAAV, AAV, bacteriophage AAV, LV, AD

rAAV

AD, LV, rAAV

Regenerative medicine

Spinal cord injury; Nonhealing diabetic foot ulcers; Neurons; Prostate cancer vaccine; Bone regeneration Dental bone regeneration; Periodontal tissue engineering Tissue engineering

Heart infarction

Heart infarction

Oncolytic therapy, Bone induction

Hepatocellular carcinoma

Bone regeneration Bone induction, Hepatocellular carcinoma

Head and neck cancer;

Angiogenesis; Skeletal muscle regeneration

Wound healing; Glue; Mucosal surfaces

Bone regeneration, infections

Cartilage regeneration

Cartilage regeneration; Central nervous system; Vascular injury; Cardiovascular disease

Tumor environment

AAV

Applications Angiogenesis; Immune shielding ; pH tuning

LV, AD, rAAV, bacteriophage

Vectors Encapsulated

Microspheres Stereolithographic printing

Apatite particles

MMP-degradable sites

Polymer blending; Cross-linking agent; Poloxamer composite

Polyurethane discs; Hydroxyapatite Mechanical properties

Gel

Alginate

Mechanical properties; Phenotype maintenance; Increased nucleus localization Mechanical properties; Phenotype maintenance Increased encapsulation efficiency; Vector Retention; Increased transduction

α-cyclodextran blend; Alginate composite; Combinatorial delivery; Allin-one vaccine α-cyclodextran blend

Gel

Poly(ethylene glycol-1-(3aminopropyl)imidazole-DLaspartic acid) Pluronic

PEGylated vector; Poly-L-lysine; Hydroxyapatite; Chitosan; Hyaluronan

Cellular infiltration; Increased vector retention; Programming pH responsivity Programming pH responsivity

Modification Effects

Macropore generation; Affinity peptides; Chitosan/Heparin nanoparticles; Poly histidine Polyethyleneimine (PEI800)

Modifications

Hydrogel

3D Structures

Poly(ethylene glycol)

Polymer System

Table 3. Polymeric Matrices Used in Matrix-Mediated Viral Delivery References

97

179

128−131

18−21,102,173−178

95

95

126,172

52,54

139,140 171

17,69,142,143,145,147−149,151,157,170

47,55,56,98−100,169

102,103,108,109,111−113,167,168

15,48,50,85,90,164−166

162

13,14,69,72,73,76,80,162,163

161

81−83,88,89,160

Bioconjugate Chemistry Review


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duction compared to Polybrene assisted transduction.75 Inclusion of small compounds within Pluronic gels has further increased transduction efficiencies, possibly due to assistance with nuclear localization of genetic cargo.80 The enhanced transduction exhibited by these materials has led to the development of improved composite gel structures which will be discussed later. PEG is widely used in biomedical applications and is regularly used to create hydrogels. PEG hydrogels are easily customizable and can serve as a model for studying factors that influence matrix-mediated delivery of viral vectors. Vector retention has been investigated through incorporation of affinity peptides or nanoparticles.81−83 Phage display identified affinity interactions with the pseudotyped vesicular stomatitis virus glycoprotein G (VSV-G) LVs, resulting in a 20-fold increase in expression.83,84 Phages with histidine at positions 4−7 showed preference to LVs, with the addition of lysine in other prominent phages.83 The viral retention exhibited by these phages suggest the presence of hydrogen bonding and/or electrostatic interactions with the LVs. Matrix retention has also been achieved using heparin-chitosan nanoparticles.82 Hydrogels containing negatively charge heparin/chitosan nanoparticles were able to retain an increased number of LVs compared to nonfunctionalized hydrogels, supported by other matrices using heparin and chitosan modifications.85 This interaction with heparin-chitosan and phage displayed peptides is likely dependent on the charge density presented to the viral capsid.82 Viral retention may be dependent on hydrogen bonding as histidine, heparin, and chitosan provide opportunity for dipole−dipole interactions. Despite the increased retention using heparin-chitosan nanoparticles, delivery of LV-VEGF from PEG hydrogels did not result in observable blood vessels after 8 weeks, possibly due to limited areas for cell ingrowth and interactions with vectors presented in dense matrices.82 The larger mesh size of macroporous PEG hydrogels (PEGmp) led to less physical entrapment of LVs, greater opportunities for transduction, cell attachment, migration, and proliferation.86,87 In vivo PEGmp hydrogels containing LV-VEGF exhibited angiogenesis after just 4 weeks with infiltration of endothelial cells through the interconnected macropores generated using gelatin porogens. PEGmps with LVs were able to support an increased number of endothelial cells compared to other formulations. Nanoporous PEG hydrogels entrapped viral vectors with similar expression levels to PEGmp, but with shorter expression periods resulting from less cellular infiltration and higher viral entrapment.88 Generally, vector retention is dependent on matrix density. Decreases in matrix density can result in cell infiltration and desirable remodeling. It may also lead to rapid vector release and insufficient temporal transgene expression for tissue regeneration. Therefore, matrices achieving appropriate vector retention and properties for tissue regeneration are crucial for effective therapeutic outcomes. PEG and PLGA matrices have been explored for the delivery of bacteriophages. PEG-maleimide hydrogels cross-linked with collagen mimetic peptides released a mixture of bacteriophages within 24 h with responsive release achieved in the presence of collagenase. In a mouse radial segment defect, phage treatments resulted in significantly lower amount of recoverable bacteria compared to controls.89 PLGA matrices manufactured via melt-processing were used to encapsulate Bacteriophage QB nanoparticles for vaccination. Matrices loaded with 10 wt % QB generated similar levels of anti-QB

for regenerative medicine and localized antitumor therapies. Each polymer system has distinct advantages depending on chain structure and properties. Matrices confer additional benefits including, but not limited to, localized release, sustained release, cellular infiltration, and mechanical support. In many instances, matrices will produce their own therapeutic response that is similar to or better than matrices with viral vectors. In the clinic, formulated collagen gels with AD encoding platelet derived growth factor beta (PDGFβ) performed similarly to collagen gels alone for treatment of nonhealing diabetic foot ulcers.19 Synthetic Polymers. Some of the first polymers used for matrix-mediated delivery are amphiphilic Pluronic (poloxamer) and Tetronic (poloxamine) copolymers composed of PEG and poly(propylene oxide) (PPO) blocks (PEG-PPOPEG) (Table 3) (Figure 1). In response to increasing temperatures PPO blocks dehydrate and polymers form micelles at low concentrations and gels of intertangled micelles at higher concentrations (Figure 2).68 These structures have

Figure 2. Poloxamers form micelles at low concentrations and gels of intertangled micelles at higher concentrations. Interactions with cell membranes can cause changes in microviscosities and membrane fluidization resulting in higher rates of transduction.

short residence times in vivo, clearing due to the highly viscous flow exhibited by these polymer types, leading to release of viral vectors. We have observed the dissolution of intratumorally injected Poloxamer 407 within 1 week in vivo.69 Tetronics, analogs of Pluronics, contain four pluronic chains branching from a charged EDTA core. The amphiphilic nature of these polymers results in increased transduction efficiencies and their wide use in matrix mediated delivery of viral vectors (Figure 2).13,14,70−75 Recently Pluronics have been shown to facilitate delivery of LVs to the central nervous system without toxicities or loss of infectivity.74,76 LVs encoding Lingo-1 short hairpin RNA have been incorporated into these gel systems to promote the functional recovery of spinal cord injuries.76 Lingo-1 is a negative regulator of axonal sprouting, myelination, and silencing may facilitate favorable remodeling upon injury.77−79 Formulation within gels required fewer vectors to achieve a therapeutic effect compared to naked vectors in vivo. Increased biomarkers for neurogenesis were observed in gel formulations along with increased sprouting of axons compared to nongel formulations.76 Formulation of Pluronic synperonics with LVs resulted in increased transF


Review

Bioconjugate Chemistry compared to a 3 injection immunization schedule in vivo, illustrating the slow release potential of this system and its ability to attenuate needs for repeated dosing.90 The use of phages in therapeutics provides another mechanism to treat infectious disease and may prove useful especially due to rising antibiotic resistance. Electrospinning utilizes high voltage gradients to shear polymer solution into nanoscale fibers capable of providing topographical cues for cells.91−93 Coaxial spinning of fibers can overcome limitations of single stream electrospinning protecting bioactive agents from harsh conditions compared to conventional single stream spinning.94 Electrospinning of polyester urethane urea (PEUU) and polyester ether urethane urea (PEEUU) into solid and core−sheath fibers influenced release of adeno-associated viruses (AAVs) with sustained release of 2 months exhibited by core−sheath matrices. Solid fibers exhibited minimal release, likely due to inactivity resulting from harsh synthesis conditions. The incorporation of PEG into the PEUU backbone led to variations in release with higher PEG contents leading to more rapid vector diffusion through swollen scaffolds. PEUU core−sheath scaffolds exhibited cellular infiltration with pores of 40 μm compared to little infiltration in solid fibers with mean pore sizes of 3 μm. In vivo PEEUU core−sheath patches with and without AAV encoding green fluorescent protein (GFP) provided functional benefit in reducing the effects of ischemic cardiomyopathy compared to naked AAVs illustrating the benefit provided by the PEEUU matrix.95 Incorporation of low MW PEG in coaxial spinning of poly(α-caprolactone) results in porogen-like effects.96 Increasing concentrations of PEG resulted in increasing rates of AD released from core-shell fibers with transgene expression of HEK 293 in vitro.97 These methods provide tunable and bendable matrices containing topographical cues for cells with sustained release of vectors. This customization allows tuning of matrix properties and resulting changes in therapeutic outcome. Synthetic polymer systems can be synthesized for customized matrix properties. Properties can be balanced to enhance temporal vector retention and cellular responses in vivo. The ease of programming makes these systems attractive for studying fundamental matrix properties. However, synthetic systems lack cues inherently found in other polymeric materials that can result in favorable remodeling and cellular proliferation. Natural Polymers. In some of the first MM delivery of vectors, alginate matrices were directly shown to limit systemic dissemination in mice upon intratumoral injections compared to free vectors, attributed to sealing of damaged blood vessels upon administration.98 LVs delivered from alginate hydrogels resulted in noticeable luciferase expression in murine hind limb muscles for 11 weeks compared to naked vectors upon administration into hind limbs. Naked vectors induced a maximal transgene expression after 14 days followed by a gradual decrease in the following 2 weeks. Peak expression of alginate loaded hydrogels was observed after 21 days and sustained for the following two months.99 The sustained expression likely results from the shielding of immune response and vector stabilization. The in vivo transgene expression follows patterns exhibited by the hydrogel degradation rates in vitro, which was tuned using binary MW polymers and partial oxidation of chains.99 Tuning alginate degradation allows customization of temporal release patterns of vectors. Furthermore, encapsulation of oncolytic ADs (oADs) in

alginate hydrogels has been shown to sustain bioactivity and vector release for an extended period. Naked vectors lost 93% ability to express GFP over 1 week compared to minimal losses by alginate formulations. In vivo oADs-alginate formulations had 1.9- (U343) and 2.4-fold (C33A) increased antitumor activity with broader tumor area expression and higher densities of expression compared to naked oADs, likely achieved by preserved bioactivity, sustained release, and viral propagation.100 Additionally, matrix-mediated immune shielding likely led to a higher degree of antitumor immunity and less innate/adaptive cell priming toward antiviral responses. Fibrin is a naturally occurring network involved in coagulation with intrinsic wound healing properties.101 Maintenance of hemostasis and hemocompatibility along with recognition motifs for endothelial cells makes it a popular choice for regenerative medicine and encapsulation of viral vectors.102,103 Fibrin matrices are composed of protofibers making up larger fibers in a hexagonal close packed crystal like structure resulting in viscous, viscoelastic matrices with water volumes of 70−90% of fiber volume (Figure 1).104−107 The use of fibrin scaffolds has illustrated therapeutic effects, with and without ADs in murine increased wound closure models.108 Release rates of ADs and LVs show strong dependence on concentration of scaffolds with sustained release greater than 1 week.103,108,109 This dependence of fibrin concentration on release and transduction of both LVs and ADs likely arises from entrapment of vectors within the matrix, either entangled within protofibers, fibers, or between fibers. Fibrin scaffolds polymerized on polyurethane discs showed maximal transduction at higher fibrin concentrations in vivo. The retention of vectors within the matrix increased target cellular interactions with entrapped vectors improving wound repair cell transduction. Maximal transduction within the matrix occurred at day 10.110 In vivo, fibrin matrices were able to retain ADs at the wound site up to 7 days, with minimal transgene expression at day 14, transducing infiltrating fibroblasts, endothelial cells, and inflammatory cells.108 Fibrinolysis occurs with the activation of plasmin from plasminogen. This conversion can occur by soluble or bound cell membrane enzymes expressed by wound cells (Figure 3). As fibrin matrices degrade, entrapped vectors are released and increase cell−vector interactions. Due to advantageous rheological properties and inherent wound healing abilities fibrin glue encapsulating viral vectors have been investigated for multiple applications.111−113 Fibrin glues provided external support for vein grafts inhibiting intimal hyperplasia. Glues have been shown to prevent overdistension and preserve distensibility in the high pressure range of the human saphenous vein.114 Sustained gene expression in perivenous applications has been achieved out to 14 days in vivo solving issues with vector dissemination and providing opportunities to ameliorate intimal hyperplasia.112,115 Further studies have illustrated the ability of fibrin glues to deliver AAVs to esophageal epithelium and promising in vitro results for cartilage engineering.111,113 The inherent cellular recognition motifs and mechanical properties exhibited by fibrin gels makes them an attractive matrix for increasing target cellular transduction, applications requiring matrix elasticity, and wound healing. Tuning of concentration and degradation can lead to variations in release patterns and increased transduction of target cells which is best evaluated in vivo. Collagen is a triple helix polypeptide chain (Gly-Pro-Xxx) with left-hand helices twisted together producing a right G


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applications.120,121 Gelatin is a denatured form of collagen with amorphous regions of interconnected coiled-coil chains and spatially ordered microcrystallites.122 The biocompatibility and osteoconductivity of gelatin has led to its use in bone regeneration.123−125 Intramuscular injections of ADs encapsulated in collagen gels resulted in bone formation after 4 weeks. This long period before formation was attributed to cellular migration and infection, which may have taken longer periods of time than that of release.102 Stereolithographic fabrication, a rapid 3D printing technology, of a nanoporous gelatin matrix was used to encapsulate human mesenchymal stem cells (hMSCs) and LV encoding bone morphogenic protein 2 (BMP2). This approach aimed to reduce unregulated bone formation by entrapping vectors and cells resulting in observable BMP2 production within 5 days and sustained production for 3 months in vitro. In vivo bone formation was slow with minimal vascularization impairing the long-term potential of this system. The inclusion of angiogenic factors may be an additional strategy to enhance regeneration.126 This rapid 3D printing technology may lead to the formation of anatomically shaped matrices with mechanical properties similar to native tissues and limitation of unregulated bone formation. Collagen blends with chitosan create hardened scaffolds that have been extensively used for bone regeneration in dental engineering.127−131 These scaffolds exhibit pore structures that appear to provide good environments for growth of human periodontal ligament cells (HPLCs). Scaffolds releasing AD encoding bone morphogenic protein 7 (BMP7) exhibited highest activity of alkaline phosphatase and expression of osteopontin and bone sialoprotein when cultured with HPLCs. Implantation into defects led to highest bone formation in ADBMP7 scaffolds at 4 and 8 weeks.131 When AD-PDGFβ were

Figure 3. Enzymatic matrix degradation can increase target cell transduction. The expression of enzymes or conversion of enzymes by target cells can lead to their infiltration into matrices while releasing entrapped viral vectors. Wound cells activate plasmin by membrane bound proteins, such as urokinase plasminogen activator receptor or tissue plasminogen activator resulting in the conversion of proenzymes to active forms in proximity of matrices.

handed coil, with quaternary structure stabilized by van der Waals, intermolecular hydrogen bonding, and covalent bonding (Figure 1).116−118 Cellular interactions with collagen provide essential signals for migration, differentiation, survival, proliferation, and anchorage.119 Collagen naturally provides support for skin, tendons, cartilage, blood vessels, and ligaments making it a viable candidate for tissue engineering

Figure 4. (A) Primary sequences of SELPs. MMP responsive sites are inserted once into SELP-815K monomer at indicated positions to produce three different responsive polymers. (B) Illustration of SELP showing the cross-linking via β sheet formation and pores created by elastin motifs. (C) Scanning electron microscopy image of SELP-815K 12 wt % hydrogel. (D) Physical characteristics of SELPs with dependence on primary polymer structure. Reprinted from Gustafson, J., and Ghandehari, H. Silk-elastinlike protein polymers for matrix-mediated cancer gene therapy (2010) Advanced Drug Delivery Reviews 62, 1509−1523, with permission from Elsevier.155 (E) Sequences of SELPs with MMP degradable site.158 (F) Physical characteristics of MMP responsive SELPs.158 H


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matrices ameliorate immune response of viral vectors, decrease hepatotoxicity, and increase safety of gene-directed enzymeprodrug therapy (GDEPT) compared to naked ADs. Localized transduction is also greater via SELP delivery, resulting in a 55fold increase in tumor/liver transduction ratio. These findings have been summarized in a previous review.155 SELP hydrogels are robust and capable of residing in vivo over 12 weeks, allowing release through a stable matrix system. Other polymers such as Poloxamer 407 undergo dissolution mediated release resulting in shorter release periods.69,156 The ability of SELPs to sustain release over 22 days results from carefully tuned physiochemical properties. Incorporation of lysine in SELP constructs (815K, 415K, 47K) may increase polymer− AD electrostatic interactions with Hexon, a major AD capsid protein (Table 1), and therefore vector retention.148,157 Prolonged matrix residence times can lead to the formation of a fibrous capsules and has prompted our lab to develop matrix-metalloprotease (MMP) responsive SELPs with varying locations of enzymatic degradable sites and properties (Figure 4E,F).69,144,158 MMPs are proteolytic enzymes that are naturally upregulated in sites of inflammation and solid cancers.159 By incorporating an MMP responsive sequence (GPQGIFGQ) into different locations of the SELP-815K backbone we can control degradation rates in inflammatory environments (Figure 4E,F).158 This degradable system was evaluated in vivo using a GDEPT approach for head and neck cancer, showing increased degradation compared to SELP-815 K, and increased mice survival from 29% to 100% over 50 days compared to control groups.142 The recombinant programing of degradation sequences within these polymers has given them a responsive release mechanism which results in specific payload unloading at inflamed sites and the ability to be naturally cleared without the formation of a fibrous capsule. Others have also illustrated the benefits of localized oADs MM delivery via SELPs. Encapsulation of oADs in SELPs results in enhanced bioactivity, with reports of up to 1000-fold greater infectivity than naked ADs after incubation for 1 week at 37 °C, explained by reported preservation of bioactivity exhibited by SELPs.17,143,170 This preservation and sustained delivery of oncolytic adenoviral vectors encoding short hairpin RNA from SELP-47K matrices may be responsible for a 1.5fold increase in antitumor efficacy, wider areas of tumor apoptosis, and higher tumor transduction compared to free vectors.143 Replication competent oncolytic vaccinia viruses (GLV-1h68) have also been encapsulated within SELP-47K matrices for treatment of thyroid carcinoma. Topical intraoperative administration of SELP-GLV-168h resulted in decreased tumor volume compared to naked vector due to increased and stable interactions with target cells rather than transient interactions exhibited by PBS formulations.170 When mechanically disrupted, SELP gels broke into particles and were capable of the highest levels of luciferase expression and tumor responses, attributed to increased matrix surface area.170 The use of SELPs in antitumor therapies has been wellestablished. SELP matrices have shown promise in tissue engineering applications but have not yet been utilized for regenerative approaches in combination with viral gene therapy.180,181 The specific incorporation of motifs designed for cellular infiltration and migration could further enhance these regenerative approaches in conjunction with viral vectors. Composite Polymer Systems. Composite polymer systems are composed of multiple polymer types to create matrices with increased mechanical or therapeutic properties. The

evaluated in these scaffolds, there was enhanced proliferation of HPLCs.130 Combination of AD-BMP2 and VEGF proteins within these scaffolds resulted in a rapid release of protein and sustained transgene expression. This formulation performed superior to scaffolds containing both AD-BMP2 and ADVEGF in canine defects around the implants.128 The rapid release of VEGF and long-term expression of BMP2 follows regenerative patterns indicated by the occurrence of angiogenesis followed by osteogenesis in bone fracture models.132−134 The combination of chitosan and collagen produces matrices with mechanical properties favorable for bone regeneration. Silk fibroin is a naturally derived polymer with high mechanical strength and has been frequently used in tissue engineering for bone regeneration.135−138 Scaffolds of this polymer have been used to incorporate AD-BMP7 and evaluated in calvarial defects.139,140 Scaffolds were capable of transfecting bone marrow derived stem cells for 14 days with production of BMP7 up to 21 days in vitro. The highest production of BMP7 occurred on day 7, and is in accordance with optimal timing of BMP7 administration for regeneration of bone within defects.139,141 In SCID mice, scaffolds containing AD-BMP7 enhanced bone formation compared to negative controls confirmed by histological staining of markers for new bone formation. The additional incorporation of bone marrow derived stem cells did not enhance in vivo efficacy suggesting AD release to surrounding environment.139 Inflammatory responses to scaffolds containing vectors were evaluated in BALB/C mice. After 1-week postimplantation there was a 2.5-fold increase of interleukin-2 compared to controls, indicating T cell receptor stimulation. TNF-α expression peaked after 1 week in vector matrices, an indication of T cell activation. Both interleukin-2 and TNF-α levels returned to normal after 4 and 2 weeks, respectively. Interleukin-6 levels did not have noticeable change throughout the study.140 These matrices are promising due to their high mechanical strength, natural breakdown, and clearance, but suffer from immunogenicity in vivo. The motifs in natural polymers can provide additional therapeutic benefits to MM viral delivery systems. Motifs for cell infiltration and enzymatic breakdown can enhance target cellular transduction. Furthermore, motifs from polymers such as silk fibroin can be utilized to engineer matrices with enhanced mechanical properties. These motifs can be incorporated in carefully designed recombinant polymer systems for exact programming of polymer properties. Recombinant Polymers. In our laboratory we have extensively studied silk-elastinlike recombinant protein polymers (SELPs) and their ability to control release of genetic materials.17,69,142−152 SELPs are composed of alternating motifs of silk (GAGAGS) and elastin (GVGVP).153 Using recombinant control, we have synthesized several variations of SELPs (Figure 4A). The elastin units result in a thermoresponsive polymer capable of forming hydrogels upon an increase in temperature and the resulting cross-linking by hydrogen bonding of silk motifs to form beta sheets (Figure 4B,C).150,154 The primary protein structure and hydrogel concentration results in varying properties (Figure 4D). Data from our lab indicates a dependence of AD release on polymer structure and hydrogel concentration. Polymers with longer elastin blocks or lower silk: elastin ratios result in increased and more complete release, due to differences in pore size and swelling ratios between the polymers (Figure 4D). SELP I


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architecture creating less semicrystalline domains and pore interconnectivity. PF-Alg resulted in less undesirable, hypertrophic differentiation in human mesenchymal stem cells compared to AlgPH155 alone.169 Recombinant elastin-like protein polymers have been combined with polycaprolactone to produce electrospun scaffolds containing AAVs. Variations in polymer blends resulted in scaffolds with varying mechanical properties, cell compatibilities, and vector transduction depending on polymer blend ratios.179 The development of polymeric matrices has led to synergism between biomaterial and gene delivery approaches to treat disease. Synthetic polymers can be designed and tuned due to vast methodologies in matrix synthesis and customization. Natural polymers are capable of mimicking native tissue properties while providing cellular signals and degradation in vivo. Recombinant polymers can utilize natural motifs for programmable mechanical properties and ability to interact with tissues. MM delivery systems can be tuned to achieve appropriate temporal release of viral vectors in addition to providing necessary matrix cues for cellular migration and proliferation.

benefits of pluronics and natural polymers have been combined into single matrices for cartilage regeneration. Pluronics/ Tetronics have been used to develop supramolecular polypseudorotaxane (PPDs) gels through inclusion of αcyclodextrin (αCD).182 These thoroughly studied structures form gels through the formation of inclusion domains and crystalline regions.183 The tunable thermal and mechanical properties exhibited by PPDs reinforce initial Pluronic/ Tetronic properties, resulting in materials with enhanced storage and elastic moduli.162,184 These supramolecular structures were evaluated for release of recombinant adenoassociated virus (rAAV) from an interpenetrating gel in combination with glycosaminoglycans abundant in the cartilage extracellular matrix, hyaluronic acid (HA), and chondroitin sulfate (CS).162,185 HA has previously been reported to exhibit high levels of biocompatibility, and the presence of HA within PPDs increased cytocompatibility.162,185 The incorporation of αCD in Pluronic- and Tetronic-CS formulations resulted in increased release rates, while the opposite was true of Pluronic- and Tetronic-HA gels. The increased release rates may be due to cross-link disruption by the charged, interpenetrating CS. The interactions between CS and αCDs would result in formation of fewer PPD gels and possible formation of Pluronic micelles acting as porogens. Tetronic gels showed the most sustained release, resulting in more dense matrices from electrostatic interactions between EDTA core (+) and the rAAVs (−).162,186 The increased matrix density is evident from higher viscosities and leads to higher diffusion resistance. The inclusion of αCD and interpretation exhibited by CS/HA resulted in altered mechanical properties and spatiotemporal release of rAAVs.162 The presence of HA increased activity of rAAVS possibly due to interactions with CD44 in mesenchymal stem cells.187 The matrix-mediated signals of HA and CS still need to be evaluated within these systems, but independent studies have shown the ability of HA and CS to modulate chondrogenesis of stem cells.188,189 Other cyclodextrin based constructs have been developed using adamantane functionalized PEG polymers, to release ADs exhibiting enhanced transgene expression of GFP compared to naked vectors and collagen matrices.190 Interpenetrating networks have further been explored by creating Pluronics and alginate matrices (PF-Alg) to transduce human mesenchymal stem cells with rAAVs toward chondrogenesis. PF-Alg contains modified rheological properties of individual polymers exhibiting a biphasic system resulting from chain−chain interactions through hydrogen bonding in addition to divalent alginate cross-linking.191,192 The biphasic nature of the PF-Alg hydrogels contains more porous structures, yet a slower release rate of rAAV, suggesting increased vector−polymer interactions. Hydrogel formation at higher temperatures created more porous structures due to entanglement of micellar PF127 acting as a porogen, releasing rAAVs more quickly. These PF-Alg systems resulted in high and stable transduction efficiencies at least 21 days. The inclusion of Pluronics in hydrogels increased gene transfer efficiencies and transgene expression levels.169 This blended construct may have resulted in multiple polymer−virus interactions, enhancing matrix retention of rAAVs. Disruption of native alginate structures by Pluronics may have resulted in modified divalent electrostatic interactions, in which Ca2+ complexes with alginate and the negatively charged rAAVs. Polymer interpenetration interrupted native alginate/Pluronic

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REMAINING CHALLENGES AND FUTURE DIRECTIONS Current MM systems for the delivery of viruses have shown promise in preclinical studies, for regenerative medicine and oncolytic therapies, requiring smaller doses than naked vectors with less immune neutralization. In clinical studies both an empty collagen matrix and matrix encapsulating AD-PDGFB showed safety and efficacy to treat nonhealing diabetic foot ulcers.18,19 Biomaterial matrices alone can have therapeutic effects depending on inherent material properties and composite systems such as interpenetrating networks have potential to increase integration with native tissues. Matrices provide opportunities to engineer regenerative microenvironments, all-in-one cancer vaccines, and localized antitumor therapies, all easily customizable through the inclusion of cells, matrix components, small molecular weight compounds, and more.80,126,163 Unique materials and formulation strategies may lead to the improvement of current polymeric MM systems. The combination of cationic gold nanoparticles and anionic tobacco mosaic virus particles generate highly organized super lattices consisting of a 2D square lattice geometry through electrostatics. This level of organization may assist with polymer engineering by defining exact colloidal requirements for material self-assembly.193 Kostiainen et al. have illustrated self-assembly using dendron−virus complexes and crystalline arrays.194,195 Elucidated matrix requirements may be exactly programmed using recombinant design and production. Further developments of MM delivery need to address specific requirements of tissue microenvironment. For example, bone regeneration requires vascularization prior to osteogenesis and matrices of high mechanical strength. Elucidating natural matrix components that provide inherent cellular signals can further enhance the therapeutic benefit provided from polymers. These motifs can be further included in recombinant systems for precise engineering of matrices or included in composite matrices through interpenetrating networks. With the advent of new methodologies, we can focus on bolstering the development of particulate systems capable of specific temporal release patterns, cell targeting, and J


Review


(7) Vandamme, C., Adjali, O., and Mingozzi, F. (2017) Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial. Hum. Gene Ther. 28 (11), 1061−1074. (8) Räty, J. K., Pikkarainen, J. T., Wirth, T., and Ylä-Herttuala, S. (2008) Gene Therapy: The First Approved Gene-Based Medicines, Molecular Mechanisms and Clinical Indications. Curr. Mol. Pharmacol. 1, 13−23. (9) Liu, T., and Kirn, D. (2008) Gene Therapy Progress and Prospects Cancer: Oncolytic Viruses. Gene Ther. 15 (12), 877−884. (10) Kaufman, H. L., Kim, D. W., Deraffele, G., Mitcham, J., Coffin, R. S., and Kim-schulze, S. (2010) Local and Distant Immunity Induced by Intralesional Vaccination with an Oncolytic Herpes Virus Encoding GM-CSF in Patients with Stage IIIc and IV Melanoma. Ann Surg Oncol, 718−730. (11) Scott, L. J. (2015) Alipogene Tiparvovec: A Review of Its Use in Adults with Familial Lipoprotein Lipase Deficiency. Drugs 75, 175− 182. (12) Beer, S. J., Hilfinger, J. M., and Davidson, B. L. (1997) Extended Release of Adenovirus from Polymer Microspheres: Potential Use in Gene Therapy for Brain Tumors. Adv. Drug Delivery Rev. 27, 59−66. (13) March, K. L., Madison, J. E., and Trapnell, B. C. (1995) Pharmacokinetics of Adenoviral Vector-Mediated Gene Delivery to Vascular Smooth Muscle Cells: Modulation by Poloxamer and Implications for Cardiovascular Gene Therapy. Hum. Gene Ther. 6, 41−53. (14) Feldman, L. J., Pastore, C. J., Aubailly, N., Kearney, M., Chen, D., Perricaudet, M., Steg, P. G., and Isner, J. M. (1997) Improved Efficiency of Arterial Gene Transfer by Use of Poloxamer 407 as a Vehicle for Adenoviral Vectors. Gene Ther. 4, 189−198. (15) Beer, S. J., Matthews, C. B., Stein, C. S., Ross, B. D., Hilfinger, J. M., and Davidson, B. L. (1998) Poly (Lactic-Glycolic) Acid Copolymer Encapsulation of Recombinant Adenovirus Reduces Immunogenicity in Vivo. Gene Ther. 5, 740−746. (16) Alden, T. D., Pittman, D. D., Hankins, G. R., Beres, E. J., Engh, J. A., Das, S., Hudson, S. B., Kerns, K. M., Kallmes, D. F., and Helm, G. A. (1999) In Vivo Endochondral Bone Formation Using a Bone Morphogenetic Protein 2 Adenoviral Vector. Hum. Gene Ther. 10 (13), 2245−2253. (17) Hatefi, A., Cappello, J., and Ghandehari, H. (2007) Adenoviral Gene Delivery to Solid Tumors by Recombinant Silk−Elastinlike Protein Polymers. Pharm. Res. 24 (4), 773−779. (18) Mulder, G., Tallis, A. J., Marshall, V. T., Mozingo, D., Phillips, L., Pierce, G. F., Chandler, L. A., and Sosnowski, B. K. (2009) Treatment of Nonhealing Diabetic Foot Ulcers with a PlateletDerived Growth Factor Gene-Activated Matrix (GAM501): Results of a Phase 1/2 Trial. Wound Repair Regen. 17 (6), 772−779. (19) Blume, P., Driver, V. R., Tallis, A. J., Kirsner, R. S., Kroeker, R., Payne, W. G., Wali, S., Marston, W., Dove, C., Engler, R. L., et al. (2011) Formulated Collagen Gel Accelerates Healing Rate Immediately after Application in Patients with Diabetic Neuropathic Foot Ulcers. Wound Repair Regen. 19 (3), 302−308. (20) Lubaroff, D. M., Konety, B. R., Link, B., Gerstbrein, J., Madsen, T., Shannon, M., Howard, J., Paisley, J., Boeglin, D., Ratliff, T. L., et al. (2009) Phase I Clinical Trial of an Adenovirus/Prostate-Specific Antigen Vaccine for Prostate Cancer: Safety and Immunologic Results. Clin. Cancer Res. 15 (23), 7375. (21) Lubaroff, D. M., Vaena, D., Brown, J., Nepple, K., Zehr, P., Griffith, K., Brown, E., Eastman, J., Zamba, G., and Williams, R. (2015) Abstract CT208: Preliminary Results of a Phase II Trial of an adenovirus/PSA Vaccine in Men with Recurrent Prostate Cancer. Cancer Res. 75, CT208−CT208. (22) Marelli, G., Howells, A., Lemoine, N. R., and Wang, Y. (2018) Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer. Front. Immunol. 9, 1 DOI: 10.3389/ fimmu.2018.00866. (23) Wills, J., and Craven, R. C. (1991) Form, Function, and Use of Retroviral Gag Proteins. AIDS 5, 639−654.

responsive unloading within diseased microenvironments.160,161

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone +1 (801) 5871566. Fax: +1(801)5816321. ORCID

Hamidreza Ghandehari: 0000-0002-9333-9964 Notes

The authors declare the following competing financial interest(s): H. Ghandehari is co-founder and shareholder of TheraTarget, a drug delivery company located in Salt Lake City, Utah.

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ACKNOWLEDGMENTS The authors acknowledge funding from the National Institutes of Health (R01CA107621 and R01CA227225). ABBREVIATIONS αCD, α-cyclodextrin; AD, Adenovirus; AAVs, adeno-associated viruses; BMP2, bone morphogenic protein 2; BMP7, bone morphogenic protein 7; CAM, chick chorioallantoic membrane; CS, chondroitin sulfate; M, D-mannonate; EDTA, ethylenediamine tetracetic acid; GDEPT, gene-directed enzyme-prodrug therapy; GFP, green fluorescent protein; HPLCs, human periodontal ligament cells; HA, hyaluronic acid; LV, lentivirus; G, L-guluronate; PEGmp, macroporous PEG hydrogels; MMP, matrix metalloproteinase; MM, matrixmediated; MW, molecular weight; oADs, oncolytic ADs; PDGFβ, platelet derived growth factor beta; PF-Alg, Pluronics and alginate matrices; PPDs, polypseudorotaxane; PEG, poly(ethylene glycol); PLGA, Poly(lactic-co-glycolic acid); PPO, poly(propylene oxide); PEEUU, polyester ether urethane urea; PEUU, polyester urethane urea; rAAV, recombinant adeno-associated virus; SELPs, silk-elastinlike protein polymers; TROMS, standard amino acid codes; total recirculation one-machine system; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; VSVG, vesicular stomatitis virus glycoprotein G

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REFERENCES

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