Acetalated Dextran: A Tunable and Acid-Labile Biopolymer with Facile

Dec 29, 2016 - Biography. Eric M. Bachelder gained extensive immunological experience while completing his graduate studies in Dr. Polly Matzinger's l...
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Acetalated Dextran: A Tunable and Acid-Labile Biopolymer with Facile Synthesis and a Range of Applications Eric M. Bachelder,* Erica N. Pino, and Kristy M. Ainslie Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States S Supporting Information *

ABSTRACT: Acetalated dextran (Ac-DEX) is a tunable acid-labile biopolymer with facile synthesis, aptly designed for the formulation of microparticles for vaccines and immune modulation. Tunability of degradation is achieved based on the kinetics of reaction and the molecular weight of the parent dextran polymer. This tunability translated to differential rates of activation of CD8+ T cells in an in vitro ovalbumin model and illustrated that acid-labile polymer can activate CD8+ T cells at an increased rate compared to acid-insensitive polymers. In addition, Ac-DEX has been used to encapsulate small molecules, deliver nucleotides, transport inorganic molecules, formulate immune modulating therapies and vaccines, and trigger pH responsive constructs for therapy. Here we highlight the properties and results of Ac-DEX nano-/ microparticles as well as the use of the polymer in other constructs and chemistries.

CONTENTS 1. Introduction 2. Adjuvant and Vaccine Delivery 2.1. Adjuvant Encapsulation 2.2. Vaccine Formulations 3. Delivery to Macrophages 4. Controlled Release 5. Devices 6. Copolymer and Other Acetalated Polymers 7. Conclusion Associated Content Supporting Information Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

and other drugs that would typically be difficult to deliver. Additionally, acetalated dextran (Ac-DEX) is an acid-sensitive polymer that degrades more rapidly at lower pH, such as in the endosome of phagocytic cells, tumors, or areas of inflammation, allowing for site-specific degradation of the polymer and subsequent release of the encapsulated therapeutic. In the reaction of dextran with 2-methoxypropene, the kinetically favored acyclic acetals will initially form, followed by the thermodynamically stable cyclic acetals. Acyclic acetals degrade rapidly during hydrolysis and result in the generation of methanol and acetone. In contrast, cyclic acetals degrade more slowly through hydrolysis and result in the generation of acetone only. This differential acetal formation was shown to be dependent on the reaction time of the polymer and to result in varying degradation rates based on the ratio of cyclic to acyclic acetals. With the differential tunability of Ac-DEX came a marked difference in T cell activation using β-galactosidase reporter cells and the model antigen protein ovalbumin. Most notably, faster degrading materials at lower pHs resulted in the most significant major histocompatibility complex class I (MHC I) and MHC II presentation. When comparing fast and slow degrading Ac-DEX to other acid-sensitive (polyacrylamide), degradable (poly(lactic-co-glycolic acid) (PLGA)), and nondegradable (iron oxide) carriers,2 fast degrading AcDEX displayed enhanced MHC I presentation and the best MHC II presentation over other carriers. CD8+ T cells are cytotoxic T cells that can kill infected cells indirectly by inducing apoptosis in the target cell, or can kill cells directly through the secretion of perforin. Therefore, CD8+ T cell

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1. INTRODUCTION Dextran is an FDA approved polysaccharide that has been used for decades as a plasma expander. The acetalation of dextran was first reported by Bachelder et al. wherein 2-methoxypropene was used to modify dextran, resulting in a biopolymer with dextran, methanol, and acetone as degradation products (Figure 1).1 The acetalation of the dextran pendant hydroxyl group results in the polymer being hydrophobic, which allows the encapsulation of drugs through emulsion chemistry, similar to what is done with polyester polymers. This acetalized polymer (Ac-DEX) facilitated the encapsulation of hydrophobic © XXXX American Chemical Society

Received: August 9, 2016

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Figure 1. Reaction scheme for the formation of Ac-DEX with 2-methoxypropene. Reprinted with permission from ref 1. Copyright 2008 American Chemical Society.

Figure 2. MHC I and MHC II class presentation of OVA with biopolymers of different degradation rates. Ac-DEX10 and Ac-DEX60 correspond to degradation half-lives of 1.7 and 16 h, respectively. Reprinted with permission from ref 2. Copyright 2009 National Academy of Sciences.

particles, have illustrated increased cytotoxicity, likely due to their highly positive zeta potentials from their cationic amines in the backbone.7 In contrast to PBAEs, POEs are very biocompatible but have relatively slow degradations at pH 5.8 Polyketals, another acid-sensitive polymer class, offer great polymer degradation control, but their difficult synthesis is less appealing than that of Ac-DEX.9 In comparison to these polymers, Ac-DEX’s inherent acid-sensitivity allows for tunable degradation profiles based on reaction time, thus allowing precise control over payload release. Since both sustained and burst release can be selectively achieved, Ac-DEX is an ideal carrier for a wide range of therapeutics. Ac-DEX is a unique biopolymer in that where other commonly used polymers degrade into acidic byproducts, all byproducts of Ac-DEX degradation are pH-neutral. This property gives Ac-DEX the following two advantages: first, a neutral pH should not adversely affect the encapsulated payloads; second, the environment surrounding Ac-DEX should not be harmed upon degradation as it could by the degradation of polymers with acidic byproducts, such as PLGA. Ac-DEX stands alone as an easily made, tunable, and acidsensitive polymer, which makes it understandable why it has been used in over 30 publications since 2008 and has been mentioned in five reviews.10−14 Here we report its application to deliver a variety of compounds, including small molecules, proteins, peptides, nucleotides, and inorganic molecules. Moreover, the most common formulation of Ac-DEX, nano-/

activation, via MHC I, is desirable to generate protective vaccine mediated immune responses against intracellular pathogens such as viruses, as well as some bacteria, parasites, and fungi. Moreover, MHC I presentation is required for the development of a therapeutic cancer vaccine. This tunability and enhanced MHC I class presentation illustrates Ac-DEX is a well-designed polymer for vaccine applications (Figure 2). Moreover, Ac-DEX particles displayed significantly greater CD4+ (MHC II) presentation, in comparison to other biomaterials, exhibiting that Ac-DEX particles cross-present to both CD4+ and CD8+ T cells, arming both the cellular and humoral responses that would be needed for many vaccines.2 Apart from enhanced activation of cellular immune responses, Ac-DEX has several other benefits when compared to other commonly used biopolymers. A primary benefit is its facile synthesis; Ac-DEX synthesis is a single vessel reaction with subsequent purification through precipitation.3 Moreover, the degradation products of Ac-DEX are pH-neutral, unlike commonly used polyesters (e.g., poly beta amino esters (PBAEs), poly(lactic-co-glycolic) acid (PLGA), polycaprolactone (PCL)) and several polyanhydrides. This allows for minimal degradation of the payload due to low pH, without the addition of excipients.4−6 Other acid-sensitive polymers have been developed for drug delivery applications, including PBAEs, poly(ortho esters) (POEs), and polyketals. PBAEs, while associated with increased cellular internalization and transfection efficiencies over PLGA B

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microparticles, has been studied extensively in vitro and in vivo and has been delivered through parenteral and needle-free routes. In addition to the particulate constructs, Ac-DEX has been incorporated into a variety of copolymers and advanced designed delivery devices which rely on the polymer’s acid sensitivity and tunable degradation rates (Supporting Information Table 1). The many publications that use Ac-DEX, as well as its broad range of applications, make it an emerging biomaterial for drug delivery.

2. ADJUVANT AND VACCINE DELIVERY The original proposed application of Ac-DEX was the formation of nano-/microparticles as a subunit vaccine. Since subunit vaccines often rely on adjuvant activity for innate immune activation,15 it goes hand-in-hand that adjuvant encapsulation in Ac-DEX would also be studied. If Ac-DEX microparticles (MPs) are of a certain size, they can passively target antigen presenting cells (APCs). Unlike most cell types in vivo, phagocytes (e.g., dendritic cells (DCs), macrophages) can internalize particles larger than 100 nm, thereby allowing uptake only by phagocytic cells if particles are greater than 100 nm.16,17 Furthermore, passive targeting of professional APCs (DCs) is possible with further sizing. Studies have shown that MPs in the range of 1−2 μm are four times more likely to be phagocytosed by CD11c+/CD11b+ cells (DCs, professional APCs) than CD11c-/CD11b+ cells (e.g., macrophages). Also, in this same size range, when observing cells extracted from the local draining lymph nodes, approximately 50 times more CD11c+CD11b− or CD11c+CD11b+ cells (DCs) phagocytosed the MPs, compared to CD11c−CD11b+ cells (macrophages). These results indicate that large particles (1−2 μm) are predominately transported by DCs from the injection site to the lymph nodes, whereas smaller particles are cleared by resident macrophages.18 Moreover, once the MPs are taken up, the acid-sensitivity of particles leads to an enhanced release of cargo through more rapid degradation of the polymer, compared to degradation at neutral pH. This combination of acid-sensitivity and passive targeting makes Ac-DEX MPs apt carriers for adjuvants and vaccines.

Figure 3. Pro-inflammatory cytokine response of a bone-marrow derived dendritic cell after 24 h of culturing with varying concentrations of media, soluble imiquimod, Ac-DEX particles encapsulating imiquimod, or empty Ac-DEX particles. Reprinted with permission from ref 19. Copyright 2010 American Chemical Society.

bioactivity in macrophages can be controlled and illustrate dose sparing.21 In addition to the encapsulation of small molecule adjuvants, nucleotide adjuvants have been formulated into Ac-DEX MPs. Two adjuvant-based nucleotides, in particular, have been used: Poly I:C, which is an agonist for TLR 3, and CpG, which activates TLR 9. In contrast to TLR 8 expression, which is uniform across species, TLR 9 activity differs between mice and humans, wherein it is significantly reduced in humans because it is limited to only plasmacytoid DCs and B cells.22 Despite this, CpG is heavily studied and therefore a practical adjuvant for vaccine formulation. In the comparison of poly I:C encapsulation with Ac-DEX versus PLGA, there was a significant increase in adjuvant encapsulation efficacy (EE) at intermediate (71K) dextran molecular weights. Also, the more quickly degrading poly I:C loaded Ac-DEX MPs resulted in increased cellular activation compared to more slowly degrading Ac-DEX and PLGA. One or both degradation rates of Ac-DEX resulted in a dose sparing compared to soluble drug.23 Increased EE in comparison to PLGA and dose sparing compared to soluble drug was also observed with the encapsulation of CpG in Ac-DEX MPs. Moreover, the viability of Ac-DEX MPs was shown to be comparable to that of PLGA MPs, indicating that increased cytotoxicity is not the cause of the increased adjuvant activity observed with Ac-DEX MPs. The encapsulation of adjuvant in Ac-DEX particles paves the way for formulation of subunit vaccines using the biopolymer.

2.1. Adjuvant Encapsulation

Primarily, toll-like receptor (TLR) agonists are the type of adjuvants that have been reported to be encapsulated in AcDEX particles. Of the TLRs studied, TLR 3 and TLR 7/8 are the most common, since these are intracellular PathogenAssociated Molecular Patterns (PAMPs) found within the cells’ phagolysosome, which is where Ac-DEX particles would reside after phagocytosis. Imiquimod, the active ingredient in Aldera cream and a TLR 7/8 agonist, was first encapsulated into AcDEX particles by Bachelder et al.19 A dose sparing of the hydrophobic adjuvant was observed in vitro in both macrophages and bone-marrow derived dendritic cells (BMDCs). A statistically significant difference in both mRNA and soluble cytokine responses was observed when BMDCs and macrophages were cultured with Ac-DEX MPs encapsulating imiquimod in comparison to empty Ac-DEX MPs and soluble imiquimod, at the same concentrations (Figure 3). 19 Resiquimod, a more hydrophilic imiquimod derivative, was later encapsulated into Ac-DEX MPs, and also displayed a dose sparing response in cytokine production in macrophages.20 Moreover, by creating a library of polymers with unique cyclic acetal coverage and molecular weight, it has been illustrated that the loading of resiquimod as well as its release and

2.2. Vaccine Formulations

The model antigen ovalbumin (OVA) was encapsulated into Ac-DEX to evaluate the effect of Ac-DEX encapsulation1 and tunability2 on MHC I and MHC II presentation using model cell lines (B3Z for MHC I presentation and KZO for MHC II presentation). Both cell lines will express β-galactosidase downstream of CD3 signaling when the immunodominant peptide of OVA is presented on APCs. The enhanced MHC I presentation (indicator of cellular activity) observed by C

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Figure 4. (A) Total IgG antibody and (B) antibody isotype generated when AJ mice were vaccinated at day 0 and 7 with Ac-DEX microparticles (MP) containing recombinant protective antigen (PA) and/or resiquimod (Resiq). A backslash (/) indicates encapsulation, whereas a plus sign (+) indicates addition of component. Statistically significant differences between groups are indicated by *. Reprinted with permission from ref 25. Copyright 2013 Springer.

and cellular immune responses greater than those of alum and lysate. Additionally, approximately 10% of mice were sterile (blood, liver, spleen) after challenge when treated with encapsulated resiquimod Ac-DEX particles, with and without antigen. This indicates a potential postexposure treatment for this bioterrorism agent.26 With the use of emulsion for both the anthrax and B. pseudomallei vaccine work, there were several inherent manufacturing limitations that needed to be addressed prior to additional development of the Ac-DEX vaccine platform. These limitations included: (1) batch processing; (2) high energy methods (e.g., sonication, homogenization) which could denature the protein antigen; (3) extended solvent and protein antigen contact times during the solvent evaporation process which can also cause denaturation of the protein; (4) limited control over the amount of drug and efficacy at which it is encapsulated; and (5) broad polydispersity of particles. The effects of protein denaturation can result in poor B cell activation, which was illustrated by the lack of neutralizing antibodies observed with the emulsion anthrax work.25 To address these limitations, an Ac-DEX MP anthrax vaccine was formulated using scalable electrospray.27 In contrast to emulsion, electrospray can be scaled by multiplexing the electrospray heads. Electrospray can have limited interaction with solvents, offers a broader range of control of EE of the payload, produces fairly monodispersed MPs, and uses slow flow rates, which translates to reduced shear stress (Figure 5). When electrospray was used to encapsulate rPA, decreased protein denaturation was observed compared to emulsion, which resulted in increased toxin neutralization of generated antibodies (Figure 5). Also due to the flexibility of particle fabrication via electrospray, we were able to encapsulate both protein and adjuvant into a single MP. In comparison to separately encapsulated adjuvant and antigen, the coencapsulated group provided decreased survival in response to a lethal challenge (Figure 5), although both groups outperformed the FDA approved anthrax vaccine formulation, BioThrax. This work illustrates the feasibility of manufacturing an Ac-DEX MP

Bachelder et al. in the initial reporting of Ac-DEX is due in part because particle cross-presentation of protein antigen has resulted in both MHC II and MHC I expression of antigen.24 Broaders et al. then illustrated that the acid-sensitivity of AcDEX generates a greater cellular response at more rapid degradation rates and in comparison to non-acid-sensitive formulations. It is this foundation in enhanced cellular responses compared to free protein as well as other biomaterials that leads to the formation of vaccines with AcDEX MPs.2 Using separate particles, a complete subunit vaccine comprised of Ac-DEX was formulated for protection against anthrax. Separate emulsion based particles were used for adjuvant and antigen because the adjuvant had poor EE using homogenization compared to sonication, but homogenization was less damaging to the protein antigen. For the study, ∼400 nm homogenized particles encapsulated recombinant protective antigen (rPA) and ∼200 nm sonicated particles loaded with resiquimod were used. Ac-DEX MPs were shown to be an efficacious vaccine carrier for both antigen and adjuvant over unencapsulated delivery. The study also indicated that high levels of total IgG antibody, significantly greater than Alum and rPA, were generated in the particle vaccine group; however, these antibodies were non-neutralizing, likely due to the denaturation of the protein during the emulsion fabrication process. Despite the poor neutralizing responses, a Type 1 helper T-cell (Th1) response was observed in both the antigen recall study as well as by the generation of IgG2 antibodies (Figure 4). This illustrates that the protection observed with the lethal challenge could be the result of a cellular immunity,25 which corresponds with the results of both Bachelder et al.1 and Broaders et al.2 The work with the anthrax vaccine paved the way for the evaluation of a Burkholderia pseudomallei vaccine for the prevention of melioidosis. Using cell lysate as a crude antigen and resiquimod, again in separate particles, vaccination with AcDEX particles was shown to significantly delay time to death, after lethal challenge, in both a rapid and more traditional vaccine schedule. The particle formulation generated humoral D

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Figure 5. (A) Scanning electron micrograph of electrosprayed particles encapsulating recombinant protective antigen (rPA). (B) Circular dichroism spectra for rPA microparticles (MPs) fabricated by emulsion (EM/rPA/MPs) and electrospray (ES/rPA/MPs). (C) Survival curves of mice (n = 10) intratracheally challenged with 12xLD50 of B. anthracis Ames spores. ES = electrospray; EM = emulsion; Resi = Resiquimod (R848); /MPs indicates encapsulation in Ac-DEX. (D) Vaccination schedule of BALB/c mice. (E) Total IgG anti-PA antibodies in mouse sera collected on Day 42. Data are displayed as the mean logarithmic transformation (base 10) of the titers (ng/mL) + 95% confidence interval (n = 10). (F) Lethal toxin (LeTx) neutralizing titers for Day 42 mouse sera. Data are reported as the mean of the log-transformed (base 10) reciprocals of the sera dilution that inhibits LeTx cytotoxicity by 50% (ED50) + 95% confidence interval (n = 5−10). Reprinted with permission from ref 27. Copyright 2016 Wiley.

vaccine platform, and the platform’s ability to protect better than the current standard vaccine. Ac-DEX particles have not only been used to stimulate an effector immune response, but they have also been used to attenuate immune responses in an antigen-specific manner. By using a tolerizing agent (e.g., dexamethasone) with an antigen (Myelin Oligodendrocyte Glycoprotein (MOG)), the costimulatory signals required for generation of an effector response are absent in the education of the T cell by the DC. This can result in antigen-specific attenuation of the immune response via

mechanisms such as the formation of T-regulatory cells, anergy, or T cell deletion. Using Ac-DEX particles to encapsulate MOG and dexamethasone into one particle, via emulsion, it was shown using a Multiple Sclerosis (MS) model (experimental autoimmune encephalomyelitis (EAE)) that mice could be taken, on average, from full hind and partial front paralysis to only exhibiting a limp tail. The application of Ac-DEX for these autoimmune therapies is reviewed by Chen et al.10 and, later, by Northrup et al.14 The application of Ac-DEX particles has gone beyond the model antigen to illustrate protective responses in E

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Figure 6. (A) Cytotoxicity, as measured with an LDH, of varying doses of empty Ac-DEX NPs, soluble AR-12, or AR-12 loaded Ac-DEX nanoparticles (NPs) when cultured with human monocyte derived macrophages. (B) Intracellular drug concentration of AR-12 in macrophages as measured with HPLC. (C) Uptake of Ac-DEX NPs when cultured with macrophages. Reprinted with permission from ref 33. Copyright 2014 Elsevier.

disease models, further illustrating the strong application of this biopolymer in a vaccine formulation.

aptly deliver HDTs that target macrophages to reduce drug toxicity and increase drug efficacy.

3. DELIVERY TO MACROPHAGES Like DCs, macrophages can be targeted by particles that are too large to be taken up by nonphagocytic cells. Moreover, since smaller particles are taken up and cleared by macrophages, one can also have a concentrated uptake in macrophages by sizing the particles between 100 nm and 1,000 nm.18 Since macrophages serve as host cells to a variety of pathogens, including viral, bacterial, parasitic, and fungal, they can act as interdiction points for therapy. By disrupting the mechanisms the pathogen usurps to reside intracellularly, pathogen growth and survival can be decreased. These host-directed therapies (HDT) are thought to mitigate the emergence of drug resistance, since they are not targeting the pathogen directly. Ac-DEX has been used to formulate one HDT, AR-12 (also known as OSU-03012). AR-12 has illustrated broad spectrum activity against multiple bacteria, viruses, and the parasite Leishmania donovani,12,28−33 and its activity has been reviewed by Collier et al.31 Compared to unencapsulated drug, AR-12 in Ac-DEX particles had significantly reduced cytotoxicity and higher intracellular drug loading. Additionally, the particles were taken up freely by human monocyte derived macrophages (Figure 6).33 In vivo, AR-12 in Ac-DEX particles displayed enhanced clearance of Francisella tularensis infection compared to the unencapsulated compound. When AR-12 in Ac-DEX particles were codelivered with a suboptimum dose of antibiotic intranasally, there was a significant increase in mouse survival compared to free drug and free suboptimum antibiotic. In the host-directed treatment of intracellular parasite, L. donovani used intravenously delivered AR-12 in Ac-DEX particles and displayed a significant reduction in parasite burden over free AR-12, both alone and when codelivered with amphotericin B. Overall, this work displays that Ac-DEX particles can more

4. CONTROLLED RELEASE Probably the broadest application of Ac-DEX is its use as a controlled release drug delivery vehicle. Similar to the payloads seen with vaccine formulations, small molecules, proteins, peptides, and nucleotides have all been encapsulated or adsorbed to Ac-DEX to achieve a desired effect. In addition, inorganic based silver carbine has been encapsulated into AcDEX to serve as an antibacterial agent.34 Many of these formulations are the traditional emulsion based nano-/microparticles that are used for both vaccine and macrophage targeting applications. By varying emulsion parameters with AcDEX, it has been shown that the encapsulation of rapamycin is dependent on the molecular weight of the base dextran,35 which corresponds to what was observed with the encapsulation of poly I:C.23 Also using traditional emulsion chemistry, it was shown that a model protein enzyme (horseradish peroxidase), encapsulated in Ac-DEX particles, had enhanced stability compared to unencapsulated protein. Moreover, AcDEX protected the enzyme and its activity from −20 to 45 °C, while PLGA melted at these higher temperatures. As expected, homogenized particles maintained better activity of the enzyme over sonicated particles (Figure 7).36 Using Ac-DEX to encapsulate proteins has advantages over polyesters and polyanhydrides because the degradation products are pH-neutral and can therefore be less damaging to the encapsulated protein. In contrast to Ac-DEX, when PLGA degrades, the core of the PLGA particle becomes extremely acidic.4 It is then not surprising that Ac-DEX has been used to deliver proteins and peptides for therapeutic treatment. Hennig et al. compared the EE of a peptide in AcDEX particles versus PLGA. They observed a decreased EE with Ac-DEX over PLGA for positively charged peptides for PLGA terminated with a carboxylic acid. The higher F

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compared their encapsulation to PLGA. Despite differences in EE, another advantage of Ac-DEX over polyesters is the tunable delivery. Suarez et al. illustrate this as an advantage in the delivery of basic fibroblast growth factor (bFGF) and myoglobin for treatment after myocardial infarction (MI). The tunability of release of these proteins afforded optimization of the release rates for the best therapeutic effect.39 The temporal control of Ac-DEX was also illustrated to deliver a hepatocyte growth factor fragment for cardioprotective therapy.40 As with the MI treatment, an optimum therapeutic effect was determined by varying the degradation rate of the polymer, underlining the importance of this Ac-DEX property. For the delivery of nucleotides, polycations have been covalently attached to Ac-DEX to facilitate ionic absorption of siRNA,41 resulting in increased knock-down compared to the free siRNA control. The increased intracellular trafficking over soluble siRNA of the Ac-DEX particles likely contributed to the increased siRNA efficacy.41 Similarly, poly beta amino esters (PBAEs) were blended with Ac-DEX to deliver plasmid. Plasmid transfection in both HeLa and RAW macrophages was found to be dependent on the weight fraction of PBAE to AcDEX.42 Other constructs of Ac-DEX have been generated to offer controlled release, including porous microparticles, composite spray dried particles, electrosprayed microparticles, electrospun mats, and electrospun mat fragments called microconfetti (Figure 8). To mimic the large porous PLGA microparticles originally developed by Edwards et al.43 Ac-DEX was made into porous microparticles, which display a significantly reduced density to volume ratio, compared to traditional emulsion particles. When modeled in a cascade impactor, the porous AcDEX particles had aerosol properties for deep lung penetration. The porous particles displayed a controlled release of the chemotherapeutic camptothecin as well as degradation-dependent release.44 To advance lung delivery using Ac-DEX, nanoparticles made of the biopolymer were loaded with either tobramycin45 or paclitaxel46 and then spray dried in a secondary matrix to form composite microparticles. Ac-DEX adjuvant microparticles, albeit not composite, have also been made through electrospray. Compared to emulsion, electrospray

Figure 7. Activity of horseradish peroxidase when (A) encapsulated in sonicated Ac-DEX particles, (B) encapsulated in homogenized AcDEX particles, or (C) unencapsulated and stored at different temperatures as a dry powder. Reprinted with permission from ref 36. Copyright 2012 Elsevier.

encapsulation for PLGA is probably due to the interaction between the positive charge of the peptide and the negative charge of the carboxylic acid.37 For neutral charged peptides and small molecules, Ac-DEX had higher EE. Other studies have encapsulated peptide into Ac-DEX particles38 but have not

Figure 8. Various constructs of Ac-DEX and their general applications.22,41−43,60 G

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Figure 9. Ace-DEX made from 2-ethoxypropene. Reprinted with permission from ref 63. Copyright 2012 American Chemical Society.

payload.55 Gu et al. coated Ac-DEX microparticles with chitosan or alginate to give alternating charges. By creating a low acid environment with gluconic acid, one product of glucose and glucose oxidase, insulin encapsulated in the AcDEX particles is released at an accelerated rate in the presence of glucose. This device was shown to attenuate blood sugar in diabetic mice.52 This is similar to the work that was done in the 1990s using poly ortho-esters as the pH-sensitive material.8 Additionally, Wang et al. has incorporated anti-PD1 antibodies into Ac-DEX for microneedle applications.56 By incorporating anti-PD1 into a polymeric microneedle, they show enhanced antibody efficacy. Also taking advantage of Ac-DEX’s acidsensitivity, two laboratories have reported the incorporation of the biopolymer into mesoporous silicon to work as valves to control the release of drug that has been absorbed into the inorganic material. Either by using different degradation rates of polymer or by exposing the composite particles to an acidenvironment, drug can be released in a more controlled manner, compared to drug absorbed on mesoporous silicon alone.53 Furthermore, Ac-DEX was used to functionalize the silicon, by attaching cell penetrating peptide to the biopolymer incorporated in the mesoporous silicon.54 Beyond mesoporous silicon, Viger et al. trapped water in Ac-DEX microparticles fabricated via electrospray. They then heated the water into vapor using a near-IR laser, which results in destabilization of the Ac-DEX matrix and more triggered drug release.55 These devices display the broad applicability of Ac-DEX.

affords a more scalable method that uses air as a continuous phase, in place of an aqueous or organic solution, resulting in increased EEs of compounds. The EE of resiquimod was increased almost 10-fold over emulsion with electrospray to form microparticles that could be delivered intravenously to treat L. donovani infection.47 A method similar to electrospray, electrospinning, has also been used to generate controlled release nanofibrous scaffolds for Ac-DEX. By electrospinning Ac-DEX with different degradation rates, controlled release of resiquimod was observed, as well as a differential effect of resiquimod on macrophages.47 The differential effect of AcDEX degradation rates aligns with the cardioprotective effects with the MI treatment with bFGF and myoglobin and also the release of saquinavir from electrospun fibers ground into injectable fragments called microconfetti.48 Collier et al. illustrated that fragments of nanofibrous Ac-DEX scaffolds that are milled can afford nearly week-long release of the protease inhibitor saquinavir when injected subcutaneously. Microconfetti could not be fabricated from PLGA or PCL, even when milled under liquid nitrogen. The high glass transition temperature of Ac-DEX (∼160−190 °C)36 allowed electrospun nanofibrous scaffolds, loaded up to 50 w/w % with saquinavir, to be milled into small injectable pieces.48 Ac-DEX has also been used in the formation of Janus particles with PLGA.49 By using electrohydrodynamic (EHD; electrospray) cojetting, Rahmani et al. formed microparticles where one-half of the particle consists of PLGA, and the other half consists of a PLGA/Ac-DEX blend. They loaded the chemotherapeutic irinotecan into the part of the particle that consisted of Ac-DEX, and they were capable of releasing in a pH-sensitive manner.50 Expanding on their previous work, Ross et al. then proceeded to use their Janus particles for the delivery of drugs to the cochleae in an animal model of cochlear implants. By using piribedil loaded microparticles, they were able to show extended release in vivo.51 These controlled release studies illustrate that the range of degradation and processability afforded with Ac-DEX is much greater than that which is observed with PLGA, leading to better controlled release systems, as included in reviews by Miladi et al.13 and Chifiriuc et al.11

6. COPOLYMER AND OTHER ACETALATED POLYMERS To further enhance Ac-DEX, functional groups have been covalently attached to the polymer and copolymers have been formed to create new micelles and other drug delivery vehicles. Initially Ac-DEX was modified with oxime chemistry to covalently link cell penetrating peptide to the particle surface. This chemistry was used to attach the peptide with a fluorophore that then displayed strong covalent attachment to the peptide.57 Also for enhanced targeting of Ac-DEX particles, mannose was ligated to the biopolymer to actively target the mannose receptor, which is highly expressed in immune cells. Mannose targeting resulted in increased MHC I presentation of OVA over conventional Ac-DEX particles.58 To cationically charge the Ac-DEX particles, spermine59 and diethylenetriamine (DET) grated poly(L-aspartic acid)60 have been covalently bound to Ac-DEX. The spermine functionalized Ac-DEX resulted in better knock-down than sham siRNA, without a marked difference in cell viability.59 For the DET grated poly(L-aspartic acid) functionalized to Ac-DEX particles,

5. DEVICES The acid-sensitive acceleration in degradation as well as AcDEX’s broadly tunable degradation make it an appealing candidate for incorporation into highly engineered devices. AcDEX has been used to more rapidly release insulin in response to changes in glucose,52 as valves in mesoporous silicon,53,54 and as vehicles to trap water for laser-assisted release of H

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Figure 10. Ace-Inulin made from 2-ethoxypropene and inulin from dahlia. Reprinted with permission from ref 64. Copyright 2016 Royal Society of Chemistry.

7. CONCLUSION In conclusion, we have reviewed the emerging biopolymer acetalated dextran (Ac-DEX). Ac-DEX has several features which make it a unique biodegradable polymer, including facile synthesis, acid-sensitivity, and tunable degradation rates. For these reasons it has emerged as a top candidate for applications in vaccines, targeted host-directed therapies to macrophages, controlled release of drug, chemotherapeutic delivery, engineered drug delivery devices, and as copolymers in drug and vaccine carriers. Ac-DEX has displayed delivery of small molecules, proteins, peptides, nucleotides, and inorganic compounds, illustrating the broad applicability of this material. Moreover, it has been used to modify inorganic mesoporous silicon, spun into nanofibrous mats, made into microconfetti, and covalently bound to other polymers to form micelles. Current uses of this biopolymer are merely the tip of the iceberg; the applications of Ac-DEX will certainly expand in the coming years.

both doxorubicin and plasmid were delivered to cancer cells with polymeric particles formed through emulsion and micelles. These carriers resulted in significant uptake of doxorubicin in cancer cells.60 In addition to the peptide-DET-Ac-DEX micelles formed, poly(ethylene glycol) (PEG) has been covalently attached in two ways to Ac-DEX to form copolymer micelles with pH-sensitive triggers. With the addition of PEG to AcDEX with varying degradation rates, micelles were formed to deliver doxorubicin. The Ac-DEX-PEG micelles released drug in a pH-sensitive manner and illustrated increased cell death compared to PEG-b-polylactide (PLA) pH-insensitive micelles at some concentrations when cultured with HeLa cells.61 PEG was also attached to Ac-DEX by adenine termination of the biopolymer and thymine termination of PEG to form a triblock polymer. Using Ac-DEX at different degradation rates resulted in differential pH-sensitive release of doxorubicin. All triblock micelles loaded with doxorubicin resulted in a significant decrease in cell viability when cultured with HeLa cells.62 In each of these cases, the acid-sensitivity and/or degradation tunability of Ac-DEX was used to help facilitate better drug delivery. In addition to copolymers, two acetalated polymers have been produced that display similar properties as the original AcDEX. Ace-DEX, which was used in several of the previously mentioned results,21,31,33,52 is formed by the reaction of dextran and 2-ethyoxypropene (leading to the use of the e in Ace over Ac), resulting in ethanol, in place of methanol, as a degradation product. Ace-DEX displays similar degradation tunability as AcDEX as well as similar cytocompatibility (Figure 9).63 Using similar chemistry, Ace-Inulin was formed (Figure 10). Whereas dextran is immunologically inert, inulin has naturally occurring immune stimulating properties, allowing Ace-Inulin to serve as its own adjuvant in vaccine formulations. Blending Ace-Inulin with Ace-DEX results in better encapsulation of protein, but decreased immune stimulatory activity, as measured through tumor necrosis factor-alpha (TNF-α) production by RAW macrophages. Overall, an Ace-Inulin blended OVA vaccine did elicit strong total IgG antibodies on order with OVA and alum.64 Similarly, silylated dextran and inulin have shown tunable properties and generation of IgG.65 These second generation Ac-DEX polymers have the same beneficial properties of Ac-DEX with some added features, including more benign degradation products and immune stimulating capabilities.

ASSOCIATED CONTENT S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrev.6b00532. Uses of Ac-DEX currently in the literature (PDF)

AUTHOR INFORMATION Corresponding Author

*Eric M. Bachelder, Ph.D., 4210 Marsico Hall, 125 Mason Farm Road, Chapel Hill, NC 27599. E-mail, ebacheld@email. unc.edu; phone, 919-962-4857. ORCID

Eric M. Bachelder: 0000-0002-8572-888X Notes

The authors declare no competing financial interest. Biographies Eric M. Bachelder gained extensive immunological experience while completing his graduate studies in Dr. Polly Matzinger’s lab at the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). During his graduate studies, he studied I

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the interaction of T-cells and dendritic cells. After completing his Ph.D. in Chemical Engineering, he joined Prof. Jean Fréchet’s lab at the University of California, Berkeley’s chemistry department for a post doc. While there, Dr. Bachelder invented various biodegradable polymers for vaccine and drug delivery applications, including Acetalated Dextran (Ac-DEX). Dr. Bachelder continued his work on Ac-DEX as an Assistant Professor at the Ohio State University and currently at the University of North Carolina at Chapel Hill. The focus of Dr. Bachelder’s research program is to develop novel drug delivery moieties for the formulation of vaccines, infectious disease treatments, and autoimmune therapies. Erica N. Pino received her B.S. in Biology from the Massachusetts Institute of Technology in 2013. Her undergraduate thesis work in the laboratories of Dr. Robert Desimone and Dr. Edward Boyden centered on characterizing heat and light propagation through rodent cortex to establish safe guidelines for optogenetic studies in nonhuman primates. Following graduation, she continued research in the Desimone lab, focusing on optogenetic inactivation of frontal eye field neurons during memory-guided saccade tasks. She is now a graduate student in the Ainslie lab, working toward her Ph.D. in the Division of Pharmacoengineering and Molecular Pharmaceutics at the University of North Carolina at Chapel Hill. Kristy M. Ainslie is an Associate Professor with appointments in the Division of Pharmacoengineering and Molecular Pharmaceutics, within the Eshelman School of Pharmacy, and the Department of Biomedical Engineering at the University of North Carolina at Chapel Hill. Her research focuses on the use of novel micro- and nanoscaled carriers for the modulation of immune responses to create vaccines for and therapies against infectious diseases. Previously, she was an Assistant Professor in the Division of Pharmaceutics and Pharmaceutical Chemistry at The Ohio State University. As a postdoctoral scholar at the University of California, San Francisco, she researched the microfabrication of oral drug delivery vehicles and the immune response of nanobiomaterials. Previously, she studied biosensors at the Naval Research Laboratory in Washington, DC, and completed a Ph.D. in Chemical Engineering at The Pennsylvania State University in the application of nanobiomaterials for antifouling implant surfaces.

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