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A novel pH- and time-based multi-unit potential colonic drug delivery system. II. Optimization of multiple response variables.

The objective of this work was to optimize a novel potential colonic drug delivery system by using a statistical procedure. Pellets were prepared by powder layering of 5-aminosalicylic acid (5-ASA) on nonpareils (0.5--0.6 mm) in a coating pan. Drug-layered pellets were coated with an inner layer of a combination of Eudragit RL and RS and an outer layer of Eudragit FS in a fluidized-bed apparatus. Central composite design was used to study the effect of three independent variables. The proportion of the more hydrophilic polymer Eudragit RL had the most significant effect on drug release--higher proportion gave faster release; the amount of inner and outer coat did not have a significant effect on the rate of drug release at either 6 or 12 h in the range studied. A second order polynomial equation was fitted to the data, and the resulting equation was used to predict the responses in the optimal region. An optimized formulation was prepared and evaluated for individual responses. The experimental values of the response variables highly agreed with the predicted values. The results demonstrated the reliability of the model in the preparation of coated pellets having predictable drug release for colonic delivery of 5-ASA.

Acrylic Resins↗

Double contrast small bowel follow-through with an acid-resistant effervescent agent.

RATIONALE AND OBJECTIVES: A new technique was developed to achieve double contrast examinations in the small bowel without intubation. METHODS: Effervescent granules and tablets were coated with an acid-resistant acrylic lacquer to provide selective enteric gas release. The coating thickness was 15% of dry weight for the granules and 1 to 4.5 mg/cm2 for the tablets. Fifty patients were examined using the method in a controlled study. All examinations were reviewed by two radiologists using a three-step quality score. The results were compared to 20 enteroclysis examinations. RESULTS: Image quality was better for the coated tablets compared with the granules (P < .01). The double-contrast small bowel follow-through (DC-SBFT) provided a better quality examination in the terminal small bowel than in the jejunum. Enteroclysis yielded better results for the jejunum, but was not superior in the terminal ileum. Average time of fluoroscopy was 477 seconds for the DC-SBFT (n = 50) compared with 952 seconds for patients receiving enteroclysis (n = 528). No side effects or adverse reactions occurred due to contrast media application. CONCLUSIONS: The results of this new method are preliminary, yet promising. For young patients and certain indications it may provide a less invasive alternative to enteroclysis.

Abdominal Pain↗

Fatigue behaviour of different dentin adhesives.

The aim of this in vitro study was to compare quasistatic and cyclic fatigue dentin bond strength of modern adhesive systems representing different generations. One hundred and fifty cavities were made in discs of freshly extracted human third molars and filled with direct resin composite restorations. Dentin adhesives of different generations (SY = Syntac Classic, multi-step system with self-etching primer; SE = Syntac Classic with additional phosphoric acid etching prior to application of the self-etching primer; SB = Scotchbond Multi-Purpose Plus, multi-step system with total etching; PE = Prime & Bond 2.1, single-step system with and without [PB] total etching) were used in combination with one hybrid composite. After 21 days of storage, 10 specimens for each adhesive system were subjected to thermocycling (1150 cycles) for 24 h and were afterwards debonded in a push-out test. Another 20 specimens were tested with cyclic fatigue according to the staircase method with 5000 cycles for each specimen. Static and cyclic push-out bond strengths, respectively, for each group were (MPa): SY 16.9 +/- 0.9 and 14.2 +/- 1.7, SE 17.5 +/- 1.8 and 14.8 +/- 3.4, SB 18.5 +/- 1.7 and 13.9 +/- 2.1, PB 14.6 +/- 2.2 and 7.2 +/- 2.4, PE 13.4 +/- 2.2 and 6.8 +/- 1.8. Both quasistatic and dynamic bond strengths revealed better values for the multi-step systems (P < 0.05). All adhesive systems tested revealed a significant fatigue behaviour which was more pronounced for the one-bottle system with a decrease of about 50% independent of additional dentin etching.

Adhesiveness↗

Endosomal escape of polymeric gene delivery complexes is not always enhanced by polymers buffering at low pH.

One of the crucial steps in gene delivery with cationic polymers is the escape of the polymer/DNA complexes ("polyplexes") from the endosome. A possible way to enhance endosomal escape is the use of cationic polymers with a pKa around or slightly below physiological pH ("proton sponge"). We synthesized a new polymer with two tertiary amine groups in each monomeric unit [poly(2-methyl-acrylic acid 2-[(2-(dimethylamino)-ethyl)-methyl-amino]-ethyl ester), abbreviated as pDAMA]. One pKa of the monomer is approximately 9, providing cationic charge at physiological pH, and thus DNA binding properties, the other is approximately 5 and provides endosomal buffering capacity. Using dynamic light scattering and zeta potential measurements, it was shown that pDAMA is able to condense DNA in small particles with a surface charge depending on the polymer/DNA ratio. pDAMA has a substantial lower toxicity than other polymeric transfectants, but in vitro, the transfection activity of the pDAMA-based polyplexes was very low. The addition of a membrane disruptive peptide to pDAMA-based polyplexes considerably increased the transfection efficiency without adversely affecting the cytotoxicity of the system. This indicates that the pDAMA-based polyplexes alone are not able to mediate escape from the endosomes via the proton sponge mechanism. Our observations imply that the proton sponge hypothesis is not generally applicable for polymers with buffering capacity at low pH and gives rise to a reconsideration of this hypothesis.

Animals↗

Bonding of restorative resins to dentine promoted by aqueous mixtures of aldehydes and active monomers.

Effective bonding between restorative resins and hard dental tissues would eliminate the need for retentive undercuts and prevent the formation of marginal gaps. While bonding to enamel has found a satisfactory solution with the advent of the acid etch technique, bonding to dentine has been more elusive. Restorative resins may bond to dentine through mechanisms involving either the inorganic or the organic constituents of the dentine. In the present work the possibility of bonding to the organic part of dentine was investigated. Since the water present in the surface of moist dentine may impede bonding, the research was focused on adhesives that are operational in aqueous environments. Aqueous mixtures of aldehydes and certain active monomers constitute such adhesives. The strength of the bond between a restorative resin and dentine was measured using the mixtures as intermediaries. To remove the smear layer the dentine was pretreated with 0.5 M EDTA, pH = 7.4. Among the aliphatic aldehydes especially propionic aldehyde and glutaraldehyde were found to be effective. Aromatic aldehydes resulted in bonds of low strength. Among the monomers investigated HEMA (hydroxyethyl-methacrylate) gave rise to the bond of highest strength. Using an adhesive based on HEMA and propionic aldehyde or HEMA and glutaraldehyde bond strengths of 15 and 18 MN/m2, respectively, were obtained. The latter adhesive significantly reduced the width of the polymerization contraction gaps between resin and dentine.

Aldehydes↗

Development of a new photocurable composite resin with reduced curing shrinkage.

OBJECTIVE: This study was conducted to evaluate the potential of a novel trifunctional methacrylate as a component of a photocurable composite resin with reduced curing shrinkage. METHODS: Tris[4-(2'-hydroxy-3'-methacryloyloxypropoxy)phenyl]methane (TTEMA) was synthesized by reacting triphenylolmethane triglycidyl ether (TTE) with methacrylic acid in the presence of 4-(dimethylamino)pyridine. Photopolymerization reactivity and volumetric shrinkage of unfilled resins based on TTEMA were investigated by Fourier transform infrared spectroscopy and density measurements, respectively, and the results were compared with those for conventional dental monomers. A three-point bending test of the TTEMA-containing composite resin was carried out. RESULTS: TTEMA was easily prepared in a good yield of 89%. Unfilled resins of TTEMA and bis-GMA, each containing 40% TEGDMA, showed similar photopolymerization reactivity. TTEMA exhibited a very low photopolymerization shrinkage of 2.09%, and 3:2 TTEMA-TEGDMA unfilled resin revealed 10% lower shrinkage than a conventional bis-GMA system containing the same amount of TEGDMA. The flexural strength of a light-activated composite resin formulated with TTEMA is comparable to that of a bis-GMA composite resin under the same conditions. SIGNIFICANCE: TTEMA is promising for application as a photocurable dental monomer due to ease of synthesis, good polymerization reactivity, and relatively low curing shrinkage.

4-Aminopyridine↗

The pH-dependent biphasic release of azidothymidine from a layered composite of PVA disks and P(MMA/MAA) spheres.

A composite device was developed to provide a biphasic drug release using poly(vinyl alcohol) (PVA) and poly(methylmethacrylate-co-methacrylic acid) (P(MMA/MAA)) spheres. Azidothymidine (AZT), an anti-HIV agent with a short biological half-life, was used as the model drug. Dynamic and equilibrium swelling of the polymers, and kinetics of AZT release from these polymers were determined in pH 1.2 and 6.8 buffer solutions. The swelling of PVA and release of AZT from PVA disks were fast and nearly pH-independent, whereas the swelling behavior and drug release kinetics of P(MMA/MAA) spheres were strongly pH-dependent. A swelling interface number for the spheres at pH 6.8 was determined to be Sw&z.Lt;1 and time dependent. Nevertheless, Fickian diffusion might also contribute to the drug release in this system. The composite disks consisting of PVA matrix and P(MMA/MAA) spheres provided prolonged (over 20 h) and more steady release profiles, differing profoundly from individual components. Such release profiles resulted from the second phase release at pH 6.8 and the presence of PVA layer. The relative drug loading in the matrix could be tailored to produce release profiles varying from a distinct bimodal release to a pseudo zero-order release with an initial burst.

Absorption↗

Mucoadhesive drug carriers based on complexes of poly(acrylic acid) and PEGylated drugs having hydrolysable PEG-anhydride-drug linkages.

We have designed a new mucoadhesive drug delivery formulation based on H-bonded complexes of poly(acrylic acid) (PAA) or poly(methacrylic acid) (PMAA) with the poly(ethylene glycol) (PEG), of a (PEG)-drug conjugate. The PEGylated prodrugs are synthesized with degradable PEG-anhydride-drug bonds for eventual delivery of free drug from the formulation. In this work we have used indomethacin as the model drug which is PEGylated via anhydride bonds to the PEG. The complexes are designed first to dissociate as the formulation swells in contact with mucosal surfaces at pH 7.4, releasing PEG-indomethacin, which then hydrolyses to release free drug and free PEG. We found that as MW of PAA increases, the dissociation rate of the complex decreases, which results in decreased rate of release of the drug. On the other hand, the drug release from PEG-indomethacin alone and from solid mixture of PEG-indomethacin+PAA was much faster than that from the H-bonded complexes. Due to the differences in the thermal stability, PMAA complex exhibited slightly faster drug release than that of the PAA complex of comparable MW. These H-bonded complexes of degradable PEGylated drugs with bioadhesive polymers should be useful for mucosal drug delivery.

Acrylic Resins↗

Constant-rate drug release from novel anionic gel beads with transient composite structure.

A new anionic composite bead system with a transient membrane-matrix structure, capable of prolonged constant-rate drug release, has been developed from suspension-polymerized poly(methyl methacrylate-co-methacrylic acid) (PMMA/MAA). These composite beads have a thin PMMA/MAA surface layer and a core consisting of the sodium salt form of the polymer (PMMA/MANa). The high loading (> 20%) of a model drug (oxprenolol HCl) that is achievable in this system from a loading solution concentration as low as 0.5% suggests the formation of a drug-polymer complex in the form of an ionic salt in the core. The release of oxprenolol from such composite beads shows an initial burst effect followed by an extended constant-rate region before leveling off. Apparently, the surface PMMA/MAA layer functions as a transient rate-controlling membrane before it is completely ionized. Because the ionization process is slow, the rate-controlling characteristics of the surface layer and the resulting constant rate of drug release are both sustained for an extended period. The unique feature of the present system is not only its high drug loading capability, but also the transient nature of the rate-controlling surface layer, which is completely ionized towards the latter part of the drug release, thus avoiding prolonged tailing of drug release that is normally associated with permanent membrane-matrix systems.

Anions↗

Complexation graft copolymer networks: swelling properties, calcium binding and proteolytic enzyme inhibition.

Graft copolymer networks of poly(methacrylic acid-g-ethylene glycol) were prepared by free radical solution UV-polymerization of methacrylic acid (MAA) and poly(ethylene glycol) monomethacrylate. Dynamic swelling studies indicated that complexation/decomplexation processes occurred due to hydrogen bonding between the carboxylic groups of the poly(methacrylic acid) (PMAA) and the ether groups of poly(ethylene glycol) (PEG). The effects of copolymer composition, graft chain molecular weight, environmental pH and ion content on network structure and gel behavior were studied. The largest change in swelling ratio and mesh size of the gel structure was observed in gels containing the highest content of PEG and the longest molecular weight PEG grafts. Complexation was greatest in hydrogels containing the longest PEG grafts and equimolar amounts of MAA and PEG. The swelling was much less pronounced in the presence of calcium chloride compared to sodium chloride which could be attributed to the complexation of calcium of the carboxylic groups in the polymer. The copolymers showed significant but less binding of calcium compared to poly(acrylates) like Carbopol 934P and polycarbophil. The P(MAA-g-EG) copolymers inhibited trypsin but to a lesser extent than the known protease inhibitors Carbopol 934P and polycarbophil. Results suggest that P(MAA-g-EG) copolymers are good drug delivery carrier candidates due to their pH-sensitive and controllable swelling behavior. Additionally, they possess some protease inhibition effect along with their bioadhesive properties which make them promising carriers for peptides or proteins.

Biocompatible Materials↗

The effect of short-term calcium hydroxide treatment on dentin bond strengths to composite resin.

The purpose of this study was to evaluate the influence of calcium hydroxide (Ca(OH)2) treatment on the bond strengths to dentin of a resin-based composite material. Two distinct dental adhesives, Prime & Bond (P&B) NT and Single Bond (SB) were used. One hundred and twenty-seven bovine incisors were mounted in acrylic, ground flat to expose middle dentin, polished to 600-grit, and randomly assigned to 10 groups: (i) 0 days, no Ca(OH)2, P&B NT; (ii) 7 days, no Ca(OH)2, P&B NT; (iii) 7 days, Ca(OH)2, P&B NT; (iv) 30 days, no Ca(OH)2, P&B NT; (v) 30 days, Ca(OH)2, P&B NT; (vi) 0 days, no Ca(OH)2, SB; (vii) 7 days, no Ca(OH)2, SB; (viii) 7 days, Ca(OH)2, SB; (ix) 30 days, no Ca(OH)2, SB; (x) 30 days, Ca(OH)2, SB. All specimens were stored in an incubator at 37 degrees C. Specimens were then retrieved and the dentin surface was rinsed with air/water spray from a triple syringe. Dentin was etched with 37% phosphoric acid (PA) for 15 s, rinsed, blot dried, and coated with adhesive according to manufacturer's instructions. The adhesive was light cured for 10 s, and Filtek Z250 was applied to the surface with a #5 gelatin capsule and light cured for 160 s. Shear bond strengths were measured for each specimen in an Instron unit at a cross-head speed of 0.5 mm min(-1). The data were subjected to anova and Duncan post-hoc tests. Mean shear bond strengths for P&B NT ranged from 8.02 to 11.79 MPa. There was no significant difference between P&B NT groups treated with or without Ca(OH)2 at any time interval. Mean shear bond strengths for SB ranged from 14.70 to 19.54 MPa. No significant difference was found between SB groups treated with or without Ca(OH)2 at 7 days. At 30 days, SB with Ca(OH)2 was significantly higher than SB without Ca(OH)2. Short-term Ca(OH)2 treatment had no detrimental effect on dentin bond strengths to the ethanol or acetone-based adhesive resin systems tested.

Analysis of Variance↗

The interaction of adhesive systems with human dentin.

PURPOSE: To investigate the interaction of six experimental and commercial bonding systems with dentin in vivo. MATERIALS AND METHODS: One-Step, Clearfil Liner Bond 2, OptiBond, Permagen with 10% phosphoric acid, Permagen with 35% phosphoric acid, and Prime & Bond were applied in standard Class I occlusal cavities in premolars scheduled for extraction for orthodontic reasons, combined either with a self-cured or with a light-cured resin composite. The teeth were carefully extracted 5 minutes after resin polymerization and fixed in 2.5% glutaraldehyde. After fixation, the specimens were dehydrated, sectioned, and processed for field-emission SEM. RESULTS: Although some systems produced gap-free intact interfaces in specific specimens, all of them showed detachment at the transition between the resin-dentin interdiffusion zone and the fluid resin placed over it. It was apparent that the presence of air-bubbles and/or thick layers of polymerized-filled fluid resin resulted in less frequent separation areas at the resin-dentin interface, providing support for the concept of the elastic cavity wall. It was also confirmed that some dentin adhesive systems do not form a thick layer over the dentin, otherwise the resin composite would not have penetrated the dentin tubules.

Adolescent↗

Properties of free films prepared from aqueous polymers by a spraying technique.

A spray method for the preparation of free films from aqueous polymeric dispersions was investigated. Free films were prepared from aqueous dispersions of methacrylic acid-ethyl methacrylate copolymer (Eudragit L 30D), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), and ethyl cellulose (EC) by a spray method and a cast method, and their mechanical properties and reproducibility were investigated. Uniform films were obtained from the dispersions of Eudragit L 30D, HPMCAS, and EC by the spray method, but films could not be formed by spraying the CAP dispersion. The tensile strength, elongation, and elastic modulus of the sprayed Eudragit L 30D films were similar to the properties of the cast films, and good reproducibility was obtained from both methods. Marked within-run variation in the mechanical properties was observed for the cast HPMCAS and CAP films, which could be due to a settling of the solid particles during the drying step. The variation in the mechanical properties of the sprayed HPMCAS films was lower and the tensile strength significantly higher than that of the cast films. There were also significant differences in tensile strength and elongation of EC films between products of the two methods. The results indicated that the spray method used to prepare the free films from aqueous polymeric dispersions provided uniform films with consistent and reproducible properties.

Acrylic Resins↗

The role of maleic anhydride in adhesive resin cements.

The adherence of resin cements depends upon, among other factors, the polar interactions across the interface: resin cement/restorative material. The polar interactions may be augmented by inclusion of polar additives such as maleic anhydride to the cement monomer. However, maleic anhydride is slowly converted to maleic acid when exposed to an aqueous environment. This may affect mechanical properties of such a cement in a negative way. It was the aim of the present investigation to analyze the role of maleic anhydride dissolved in the monomer of resin cements. The resin cement monomers used were common methacrylates, to which maleic anhydride in amounts of up to 30 mol% was added. Polymerization initiators were included to make the materials dual curing. Finally, the preparations were mixed with silanated fillers. The adherence energy of the cements bonded to a chromium-cobalt alloy was assessed by means of the double cantilever beam test. The strength and stiffness of the resin cements were recorded at base line and after two months storage in water. The initial adherence energy increased by a factor of about two as a result of addition of maleic anhydride. However, resin cements containing maleic anhydride suffered significant reductions in long-term adherence, strength and stiffness. These reductions were particularly pronounced in non-irradiated specimens. The use of resin cements containing maleic anhydride is not a viable means of conveying adhesiveness to resin cements.

Adhesiveness↗

The shear bond strengths of stainless steel and ceramic brackets used with chemically and light-activated composite resins.

Since the introduction of ceramic brackets to orthodontic therapy, a need has arisen to test the manufacturer's claims regarding these brackets. Forty-eight noncarious human canine teeth were divided equally into groups A to D. Brackets were bonded to these teeth with the use of the acid-etch technique and a composite resin according to the manufacturer's instructions. The combination within each group was as follows: A = stainless steel brackets and chemically cured resin; B = ceramic brackets and chemically cured resin; C = ceramic brackets and light-cured resin; D = stainless steel brackets and light-cured resin (via transillumination). After curing, the teeth were stored for 1 week in distilled water at 37 degrees C. The Instron machine was used to test the shear bond strengths of the brackets to the teeth. The brackets were individually tested to failure of the bond, which was recorded along with the site of fracture. The conclusions are as follows: (1) all combinations produced shear bond strengths that were greater than those that are considered clinically acceptable, (2) the ceramic groups exhibited a significantly higher bond strength than that of the stainless steel group, and (3) enamel fractures occurred among the B group in 40% of the samples tested in that group. It is thus apparent that a fracture of enamel is a real possibility during therapy or at debonding of the ceramic brackets, especially if the tooth is nonvital.

Analysis of Variance↗

Synthetic cinchonidine receptors obtained by cross-linking linear poly(methacrylic acid) derivatives as an alternative molecular imprinting technique.

A molecular imprinting approach to construct synthetic receptors was examined, wherein a linear pre-polymer bearing functional groups for intermolecular interaction with a given molecule is cross-linked in the presence of the molecule as a template, and subsequent removal of the template from the resultant network-polymer is expected to leave a complementary binding site. Poly(methacrylic acid) (PMAA) derivatized with a vinylbenzyl group as a cross-linkable side chain was utilized as the pre-polymer for the molecular imprinting of a model template, (-)-cinchonidine. Selectivity of the imprinted polymer was evaluated by comparing the retentions of the original template, (-)-cinchonidine and its antipode (+)-cinchonine in chromatographic tests, exhibiting a selectivity factor up to 2.4. By assessment of the imprinted polymers in a batch mode, a dissociation constant at 20 degrees C for (-)-cinchonidine was estimated to be K (d) = 2.35 x 10(-6) M (the number of binding sites: 4.54 x 10(-6) mol/g-dry polymer). The displayed affinity and selectivity appeared comparable to those of an imprinted polymer prepared by a conventional monomer-based protocol, thus showing that the pre-polymer, which can be densely cross-linked, is an alternative imprinter for developing template-selective materials. (-)-Cinchonidine-imprinted polymers were prepared and assessed using the pre-polymers bearing different densities of the vinylbenzyl group and different amounts of the cross-linking agent to examine the appropriate density of the cross-linking side chain that was crucial for developing the high affinity and selectivity of the imprinted polymers.

Cinchona Alkaloids↗

Biocompatible in-tube solid-phase microextraction coupled to HPLC for the determination of angiotensin II receptor antagonists in human plasma and urine.

A poly (methacrylic acid-ethylene glycol dimethacrylate, MAA-EGDMA) monolithic capillary was used for the in-tube solid-phase microextraction (in-tube SPME) of several angiotensin II receptor antagonists (ARA-IIs) from human plasma and urine. Under the optimized extraction condition, the protein component of the biological sample was flushed through the monolithic capillary, while the analytes were successfully trapped. Coupled to HPLC with fluorescence detection, this on-line in-tube SPME method was successfully applied for the determination of candesartan, losartan, irbesartan, valsartan, telmisartan, and their detection limits were found to be 0.1-15.3ng/mL and 0.1-15.2ng/mL in human plasma and urine, respectively. The method was linear over the range of 0.5-200ng/mL for telmisartan, 5-2000ng/mL for candesartan and irbesartan, 10-2000ng/mL for valsartan, and 50-5000ng/mL for losartan with correlation coefficients being above 0.9985 in plasma sample and above 0.9994 in urine sample. The method reproducibility was evaluated at three concentration levels, resulting in the R.S.D. <7%. The poly (MAA-EGDMA) monolithic capillary was demonstrated to be robust and biocompatible by using direct injections of biological samples.

Angiotensin Receptor Antagonists↗

Photochemically enhanced adenoviral transduction in a multicellular environment.

Photochemical internalization (PCI) enhances adenovirus (Ad) transgene expression in a variety of cell lines in vitro. However, measurements of the photochemical effect on transduction in multicellular environments are lacking. In this study, spheroids of DU 145 prostate cancer cells were used as a model to evaluate Ad serotype 5 (Ad5) transduction in a multicellular environment in response to PCI treatment. Furthermore, the Ad5 was coated with poly(2-methyl-acrylic acid 2-[(2-(dimethylamino)-ethyl)-methyl-amino]-ethyl ester) (pDAMA) to evaluate whether physicochemical properties such as charge and size of viral vectors affect transduction of photochemically treated spheroids. Spheroids incubated with photosensitizer TPPS(2a) (1 microg ml(-1)) and infected with adenovirus contained 3-fold higher percentage of reporter gene expressing cells after exposure to blue light (0.42 J cm(-2)) compared to no light, as analysed by flow cytometry of dissociated spheroids two days after treatment. The cells within the infected spheroids were further divided into three sections corresponding to the interior, intermediate and peripheral layers of the spheroids. This was performed by staining the spheroids with a diffusion-limited dye prior to dissociation. Transduction of cells within photochemically treated and untreated spheroids was heterogeneous, with a radial reduction of transgene expression towards the inner section of the spheroid. The coating of Ad with pDAMA induced up to 2-fold decrease in transduction of cells in the interior section of spheroids compared to uncomplexed Ad, while transduction of the peripheral section remained unchanged. The decrease in transduction could be related to reduced diffusion due to the size of the Ad-pDAMA complexes.

Adenoviridae↗