Dextrin-based Drug Delivery Systems

Modern technological advances opened a window of opportunities for a diverse range of engineered constructs. Table 2.2 lists a variety of mechanism by which dextrin can be customized to partake in several different constructs for drug delivery purposes, evidencing its versatility. Modifications such as succinylation, oxidation, crosslinking, hydrophobic or physical interactions, have been employed to produce polymer–drug conjugates, nanogels, NPs, other nanocomplexes and HGs.

Esterification is a very popular starch modification ¹⁵⁹, being succinylation the most preferable method for the introduction of carboxyl groups (−C(=O)OH) along the backbone chain with precise tunability ¹⁶⁰. The process includes the reaction of a carboxylic acid (succinic anhydride) with an alcohol (starch derivative), producing an ester. Succinic acid is a four-carbon cyclic structure dicarboxylic anhydride, highly reactive toward nucleophiles. Attack of a nucleophile at one carbonyl group opens the anhydride ring forming a covalent bond, whereas the second carbonyl group end results in a free carboxylic acid. For non-aqueous reactions, dimethylaminopyridine (DMAP) is regularly used as the organic catalyst (proton acceptor) to activate starch, making it nucleophilic, and to react with succinic anhydride to form a succinyl pyridinium intermediate, which then reacts with starch, finally culminating in starch succinate ¹⁶¹. Then, a covalent link can be created between carboxylic acid (−C(=O)OH) and free amines (−NH2) of bioactive molecules by carbodiimide chemistry. Dextrin-LL18 conjugates reduced free peptide antimicrobial activity from a 50

% cytotoxic concentration (CC50) of 0.35± 0.01 µM to 1.77 ± 0.25 µM, though restoring it to 0.48 ± 0.03 µM after enzymatic breakage of the dextrin glycosidic bonds by α-amylase ⁹⁰. This suggests an initial

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shield effect, the peptide activity being restored upon release resulting from dextrin degradation.

Consistently, this shield-and-restoring effect was also reported for dextrin conjugation to epidermal growth factor with potential for tissue repair therapy 152,162,163, and colistin ^164,165.

Another strategy relies on grafting hydrophobic moieties in the dextrin backbone, resulting in self-assembled structures with hydrophobic cores suitable for the stabilization of other hydrophobic compounds. For instance, grafting vinyl acrylate groups in dextrin backbone by transesterification was used to prepare a nanocarrier for IL-10 ¹⁶⁶, superparamagnetic iron oxide NPs ¹⁶⁷, and for curcumin ¹⁶⁸ delivery.

Oxidation with sodium periodate has been the preferable method to introduce multiple aldehydes in dextrin, in which vicinal diols (in C2 and C3 position) can be cleaved by strong oxidants into its corresponding carbonyl compounds ¹⁵⁹ (Figure 2.13). These aldehydes are then suitable for dynamic Schiff base bonds, which confer a stimuli responsive feature as it disintegrates upon acid hydrolysis ^149,150, being mostly used in the development of pH sensitive HGs. The dialdehydes resulting sodium periodate oxidation can be crosslinked through amines (−NH²) present in crosslinkers such as hydrazides 91,92,169-171. Dialdehyde dextrin can be used itself as an alternative low toxicity crosslinker for other polymer-based HGs, binding to chitosan amines (−NH2) for instance ¹⁷², or to gelatin amines ¹⁷³, crosslinking being further reinforced with hydrogen bonding with borax. Apart from HGs, one example is the use of oxidized dextrin (aldehydes) coated onto the surfaces of silica NPs (amines) via pH-sensitive Schiff bonds ¹⁵⁰. The functional NPs effectively prevented premature drug release under physiological conditions, but rapidly released the drug in the presence of (acidic) cancer environment.

Dextrin also offers plenty of strategies in its native form for the development of drug delivery systems, without requiring previous chemical modifications. Hydrophobic amphotericin B was solubilized in native hydrophilic dextrin by dissolution in alkaline borate buffer, followed by freeze-drying or nano spray-drying methods, resulting in self-assembled nanocomplexes with superior selectivity index compared to free drug

174. Dextrin provided a simple and inexpensive nanocarrier for amphotericin B. The hydroxyl groups from dextrin and from naringin are able to react with aldehydes of glyoxal, a crosslinker dialdehyde, via the formation of acetal bonds ¹⁷⁵. This dextrin-based nanocarrier improved naringin's therapeutic action against carcinoma-isolated HepG2, by activating anti-inflammatory responses and inducing apoptosis.

Once more as a platform for anticancer treatment, unmodified dextrin was used as a coating of halloysite nanotubes by physical adsorption, upon mixing, sonication and vacuum-facilitated deposition, conferring an enzyme-activated intracellular delivery action ¹⁷⁶. Unmodified dextrin is also useful for HGs development, making use of the biding affinity between carbohydrates and binding domains of

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biding modules ¹⁷⁷, or benefiting of a bond between dextrin hydroxyl groups (−OH) and isocyanate-terminated prepolymer (−NCO)¹⁷⁸. In a different strategy, polypyrrole- and dextrin-based nanocomposites were synthesized by in situ polymerization of polypyrrole (−NH) in presence of dextrin (−OH) activated in acidic medium ¹⁷⁹. Dextrin provided inexpensive biodegradability and biocompatibility to a composite with a poor mechanical property and processability, though with antioxidant and antibacterial activities.

In the preparation of scaffolds or other bone filling agents, dextrin is of interest as a pore-inducing agent

180,181 and for mechanical adjustments (e.g. viscosity, homogeneity) 153,180-182, having implications on cell anchorage and activity ¹⁸⁰. In these cases, dextrin is typically used in its native form.

Overall, dextrin can incorporate both hydrophilic and hydrophobic therapeutics by covalent bond or other non-covalent interactions, not necessarily requiring a previous chemical modification. Several constructs can be designed by a plethora of mechanisms on the basis of its functional groups. Degradation and drug release may be fine-tuned taking advantage of pH, enzymes or degree of modification.

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Table 2.2 – Summary of constructs making use of dextrin versatility to create novel constructs/systems for biomedical purposes.

Construct/

System

Therapeutic of interest

Dextrin modification Reaction mechanism Utility

Conjugates

90,152,162-165

Peptides (colistin, LL18); epidermal growth factor.

Introduction of carboxyl groups (−CH=O) by succinylation.

Covalent bond between carboxyl (−CH=O) from modified-dextrin and amine (–NH2) from bioactive molecule, by carbodiimide chemistry.

Shield-and-restoring effect: sustained release by enzymatic activation.

Coating onto silica NPs (MSNs)

150

Doxorrubicin. Oxidation (−CH=O) via sodium periodate

DAD was conjugated on the surface of MSNs as caps by reaction between DAD aldehydes

(–C(=O)OH) and amines (–NH2) of MSNs through Schiff-base reaction.

Triggered release at specific site (pH-sensitive);

control premature drug release.

Nanogels

166-168,183

Curcumin; IL-10 and iron oxide NPs.

Grafting of hydrophobic vinyl acrylate domains, by transesterification, resulting in an amphiphilic, self-assemble, system.

Hydrophobic–hydrophobic interactions.

Drug internally stabilized through the

hydrophobic domains. Solubilization of hydrophobic molecules within the hydrophobic core of self-assembled hydrophobized dextrin.

siRNA.

Dextrin was succinylated (–

C(=O)OH), then firstly linked to cystamine, and secondly to arginine via carbodiimide chemistry (carboxyl-amine bonds), then finally thiolated with dithiothreitol.

siRNA entrapped by charge condensation with positive arginine residues of modified dextrin. Nanogels formed by disulfide crosslinking as well as the electrostatic adsorption effect with siRNA.

Bioreducible responsive behavior (accelerated siRNA release in a bioreducible intracellular environment, as in tumor cells, remaining stable under physiological conditions.

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Conductive Nanocomposites

179

Polypyrrole. No modification. In situ polymerization of polypyrrole, in the presence of dextrin activated in acidic medium.

Confer (inexpensive) biodegradability to a conductive nanocomposite with antioxidant and antibacterial activities.

Nanocomplexes¹

74 Amphotericin B. No modification. Physical interaction.

Solubilize hydrophobic drug, shield toxicity and increase therapeutic index. Simple method and inexpensive formulation.

NPs

175 Naringin. No modification.

Hydroxyl groups (–OH) from dextrin and from naringin react with glyoxal

(crosslinker) aldehydes (−CH=O) via the formation of acetal bonds.

Effective carrier for long-term naringin delivery, providing higher anticancer potency compared to free naringin.

Dextrin-clogged nanotubes

176

Triazole dye

brilliant green. No modification.

Physically-adsorbed dextrin layer on nanotubes, via vacuum-facilitated deposition.

Selective anticancer drug delivery; enzyme-responsive coating to clog the tube opening until the cell absorbs these nanocarriers and induce release only inside the cells.

Hydrogels

91,92,169-173,177,178

Recombinant protein made of

RGD and SB). No modification. Binding affinity between the binding domain of SMB and dextrin.

Adsorb the RGD sequence to the hydrogel surface; improved adhesion of fibroblasts (>

30 %) to the hydrogel.

Bone substitutes;

proteins; stem cells; urinary bladder matrix, VH, LL18.

Oxidation with sodium periodate; crosslinking with adipic hydrazide agent.

Schiff-base reaction - hydrazone bonds – between DAD (−CH=O) and hydrazide (–

NH²).

Injectability; moldability; drug administration;

mechanical strength reinforcement.

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Oxidation with sodium periodate, then used as crosslinker itself for an agarose and chitosan-based hydrogel.

Schiff base reaction between dextrin (−CH=O) and chitosan (−NH2), and physical interaction with agarose.

Low cytotoxic crosslinking agent; stiffness strongly influenced by the degree of oxidation;

adjustment of physico-chemical and elastic properties, with implications on cell attachment and proliferation.

Oxidation with sodium periodate; borax as crosslinker.

By means of (reversible) imide bonds between dextrin (−CH=O) and gelatin (–

NH2); hydrogen bonds between dextrin (−OH) and hydrolyzed borax (−OH);

Injectable and self-healing properties, degradability and blood compatibility.

Dexamethasone. No modification.

Grafting of polyurethane on dextrin occurs through the chemical reaction between isocyanate-terminated prepolymer (−NCO) and the hydroxyl group (−OH) of dextrin forming a urethane linkage (−NHCOO−).

Hydrophobic interaction between drug and hydrogel.

Different graft density to control the

hydrophilic–hydrophobic balance for regulated drug delivery.

LL18, LLKKK18; DAD, dialdehyde dextrin; NPs, nanoparticles; MSNs, mesoporous silica nanoparticles, RGD, Arg-Gly-Asp peptide; SBM, starch-binding module;

siRNA, small interfering ribonucleic acid (siRNA); VH, vancomycin hydrochloride.

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