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.2012 Nov 12;13(11):3627-40.
doi: 10.1021/bm301583s. Epub 2012 Oct 29.

Dextran vesicular carriers for dual encapsulation of hydrophilic and hydrophobic molecules and delivery into cells

Affiliations

Dextran vesicular carriers for dual encapsulation of hydrophilic and hydrophobic molecules and delivery into cells

P S Pramod et al. Biomacromolecules..

Abstract

Dextran vesicular nanoscaffolds were developed based on polysaccharide and renewable resource alkyl tail for dual encapsulation of hydrophilic and hydrophobic molecules (or drugs) and delivery into cells. The roles of the hydrophobic segments on the molecular self-organization of dextran backbone into vesicles or nanoparticles were investigated in detail. Dextran vesicles were found to be a unique dual carrier in which water-soluble molecules (like Rhodamine-B, Rh-B) and polyaromatic anticancer drug (camptothecin, CPT) were selectively encapsulated in the hydrophilic core and hydrophobic layer, respectively. The dextran vesicles were capable of protecting the plasma-sensitive CPT lactone pharmacophore against the hydrolysis by 10× better than the CPT alone in PBS. The aliphatic ester linkage connecting the hydrophobic tail with dextran was found to be cleaved by esterase under physiological conditions for fast releasing of CPT or Rh-B. Cytotoxicity of the dextran vesicle and its drug conjugate were tested on mouse embryonic fibroblast cells (MEFs) using MTT assay. The dextran vesicular scaffold was found to be nontoxic to living cells. CPT loaded vesicles were found to be 2.5-fold more effective in killing fibroblasts compared to that of CPT alone in PBS. Confocal microscopic images confirmed that both Rh-B and CPT loaded vesicles to be taken up by fibroblasts compared to CPT alone, showing a distinctly perinuclear localization in cells. The custom designed dextran vesicular provides new research opportunities for dual loading and delivering of hydrophilic and hydrophobic drug molecules.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Dextran vesicular approach for delivery of hydrophilic and hydrophobic drugs (or molecules) into cells.
Figure 2
Figure 2
1H and13C NMR spectra of dextran-PDP amphiphilic polymers (in DMSO-d6).
Figure 3
Figure 3
DLS histogram (a) and HR-TEM (b) of DEX-PDP-5 in PBS. DLS histogram (c) and HR-TEM (d) of DEX-CAR-5 in PBS. (e) AFM phase images of DEX-PDP-5 vesicular structure. (f) Static light scattering data for DEX-PDP-5 in PBS at 25 °C (0.5 mg/mL). The vials showed the solution containing the vesicles in water.
Figure 4
Figure 4
Schematic representation of the encapsulation of Rhodamine-B in the vesicle and their presence in the dialysis tube (a). Photographs of vials containing the dextran derivatives with Rh-B after 48 h of dialysis (b) and their solution color under photoexcitation (c). DLS histograms (d) and HR-TEM (e) of Rh-B loaded DEX-PDP-5 in PBS (6.2 × 10−5 M). Confocal microscopic image of Rh-B loaded vesicles (f) in PBS (6.2 × 10−3 M).
Figure 5
Figure 5
Schematic representation of the encapsulation of camptothecin in the vesicle and its DLS histograms (a). HR-TEM image of the CPT loaded vesicles (b). The inset showed the expanded image of the vesicles with well-defined corona with respect to vesicular assemblies. HPLC traces of CPT in PBS and encapsulated in the vesicle in the carboxylic and lactone forms (c). Absorbance and fluorescence spectra of CPT loaded vesicles in PBS (d).
Figure 6
Figure 6
Schematic drug release of vesicular scaffolds under normal dialysis and in the presence of esterase enzymes. The photographs of the vials showed the formation of precipitate over a prolonged storage of the CPT loaded (a) and Rh-B loaded vesicles (b) in the presence of esterase. The left and right of the vials are corresponding to the Rh-B or CPT loaded vesicles in the absence or presence of esterase, respectively. Cumulative drug release of CPT, CPT loaded vesicles, and Rh-B loaded vesicles (c). The schematic model represents the disassociation of vesicular scaffolds in the presence of esterase (d).
Figure 7
Figure 7
Cytotoxicity data of DEX-PDP-5 at various concentrations (a) in MTT assay. Cytotoxicity data of CPT and CPT loaded DEX-PDP-5 vesicles in MTT assay (b). Confocal image and quantitation of CPT, DEX-PDP-5, and DEX-PDP-CPT vesicles uptake in cells (c). Localization of CPT loaded DEX-PDP-5 vesicles in cells (d).
Figure 8
Figure 8
Endocytosis of DEX-PDP-Rh-B in mouse fibroblasts. (a) Endocytosed DEX-PDP-Rh-B shows a distinct perinuclear localization in mouse fibroblasts. Actin cytoskeletal network in cells is stained with phalloidin. (b) Fluorescence confocal images of control untreated cells and cells incubated with DEX-PDP-Rh-B for 2 and 24 h were recordered, their spread area mapped, and fluorescence intensity in the cell area analyzed using the Image J densitometric software. Mean of fluorescence intensities is represented in the graph.
Scheme 1
Scheme 1. Synthesis of Dextran Derivatives
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