Cellular uptake of glucoheptoamidated poly(amidoamine) PAMAM G3 dendrimer with amide-conjugated biotin, a potential carrier of anticancer drugs

Uram, Łukasz; Szuster, Magdalena; Filipowicz, Aleksandra; Zaręba, Magdalena; Wałajtys-Rode, Elżbieta; Wołowiec, Stanisław

doi:10.1016/j.bmc.2016.11.047

Cited by 29 publications

(36 citation statements)

References 32 publications

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“…Here, we have prepared series of PAMAM G3 dendrimers modified by stepwise substitution of primary amine groups by amide bonds in reaction with d-glucoheptono-1,4-lactone, which was previously used to eradicate amine groups [9,10]. Such substitution allows to provide six hydroxyl groups per one glucoheptoamide substituent and to keep low molecular weight dispersity contrary to commonly used PEG-ylation [4] as well as to maintain very good water solubility of modified PAMAM [9][10][11]. We examined partially glucoheptoamidated G3 by monitoring the molecular size, ζ potential, electrophoretic mobility, and elasticity of the conjugates by differential scanning calorimetry in order to tune the conjugate physical properties.…”

Section: Introductionmentioning

confidence: 99%

Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates

et al. 2020

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Third-generation poly(amidoamine) dendrimer (PAMAM) was modified by stepwise primary amine group amidation with d-glucoheptono-1,4-lactone. The physicochemical properties of the conjugates—size, ζ potential in lysosomal pH 5 and in neutral aqueous solutions, as well as intramolecular dynamics by differential scanning calorimetry—were determined. Internalization and toxicity of the conjugates against normal human fibroblasts BJ were monitored in vitro in order to select an appropriate carrier for a drug delivery system. It was found that initial glucoheptoamidation (up to 1/3 of amine groups of neat dendrimers available) resulted in increase of conjugate size and ζ potential. Native or low substituted dendrimer conjugates accumulated efficiently in fibroblast cells at nontoxic 1 µM concentration. Further substitution of dendrimer caused consistent decrease of size and ζ potential, cell accumulation, and toxicity. All dendrimers are amorphous at 36.6 °C as determined by differential scanning calorimetry (DSC). The optimized dendrimer, half-filled with glucoheptoamide substituents, was applied as carrier bearing two covalently attached cytisine molecules: a rigid and hydrophobic alkaloid. The conjugate with 2 cytisine and 16 glucoheptoamide substituents showed fast accumulation and no toxicity up to 200 µM concentration. The half-glucoheptoamidated PAMAM dendrimer was selected as a promising anticancer drug carrier for further applications.

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Section: Introductionmentioning

confidence: 99%

Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates

et al. 2020

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“…62,63 This increased with incubation time and reached a steady state within the cells after 24 and 48 hrs at low and high concentrations, respectively. 63 Conjugated dendrimers also had lower cytotoxicity in normal fibroblasts and SCC-15 (squamous cell carcinoma) cancer cell line with higher cytotoxic effects in U-118MG (human glioblastoma) cell lines. Moreover, cancer cell lines also had higher rates of cellular uptake of the biotin-conjugated dendrimers throughout the 24 hrs of incubation.…”

Section: Gl261mentioning

confidence: 95%

“…62 While β-CD offers an excellent and highly specific mode of targeted cancer therapy, Uram and colleagues (2017) examined the use of folate and biotin as another potential surface modification for cell-specific targeting. 63 Cancer therapy research often examines the use of folate and biotin due to overexpression of folate-binding protein and increased biotin receptors in cancer cell membranes for the rapid and uncontrolled proliferation of cancer cells. Given this principle, Uram and colleagues (2017) used G3 PAMAM dendrimers functionalized with four biotin equivalents attached to the amine shell.…”

Section: Recent Progress In Pamam Dendrimer Technology Surface and Comentioning

confidence: 99%

“…Given this principle, Uram and colleagues (2017) used G3 PAMAM dendrimers functionalized with four biotin equivalents attached to the amine shell. 63 Biotinylated bioconjugates are known to have lower cytotoxicity and 3-4 times higher cellular uptake than non-biotinylated dendrimer conjugates. This is important as unmodified PAMAM dendrimers are known to be cytotoxic and increase in cytotoxicity with increased size and cationic character of their surface.…”

Section: Recent Progress In Pamam Dendrimer Technology Surface and Comentioning

confidence: 99%

“…Overall, the biotinylated conjugated G3 PAMAM dendrimers were less cytotoxic compared to the unconjugated dendrimers and had significantly greater cellular uptake into cancer cells. 63 The ability to manipulate the net charge and properties of PAMAM dendrimers through surface modification and conjugation allows them to serve as both a delivery system and a therapeutic itself. While DNA and siRNA are often conjugated to the surface of PAMAM dendrimers, other common biomolecules that are utilized are ligands, peptides, PEG, antibodies, antioxidants, and plasmids ( Figure 2).…”

Section: Gl261mentioning

confidence: 99%

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<p>PAMAM Dendrimer Nanomolecules Utilized as Drug Delivery Systems for Potential Treatment of Glioblastoma: A Systematic Review</p>

Fana

Gallien

Srinageshwar

et al. 2020

IJN

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Glioblastoma (GB) is a grade IV astrocytoma that maintains a poor prognosis with respect to current treatment options. Despite major advancements in the fields of surgery and chemoradiotherapy over the last few decades, the life expectancy for someone with glioblastoma remains virtually unchanged and warrants a new approach for treatment. Poly(amidoamine) (PAMAM) dendrimers are a type of nanomolecule that ranges in size (between 1 and 100 nm) and shape and can offer a new viable solution for the treatment of intracranial tumors, including glioblastoma. Their ability to deliver a variety of therapeutic cargo and penetrate the blood-brain barrier (BBB), while preserving low cytotoxicity, make them a favorable candidate for further investigation into the treatment of glioblastoma. Here, we present a systematic review of the current advancements in PAMAM dendrimer technology, including the wide spectrum of dendrimer generations formulated, surface modifications, core modifications, and conjugations developed thus far to enhance tumor specificity and tumor penetration for treatment of glioblastoma. Furthermore, we highlight the extensive variety of therapeutics capable of delivery by PAMAM dendrimers for the treatment of glioblastoma, including cytokines, peptides, drugs, siRNAs, miRNAs, and organic polyphenols. While there have been prolific results stemming from aggressive research into the field of dendrimer technology, there remains a nearly inexhaustible amount of questions that remain unanswered. Nevertheless, this technology is rapidly developing and is nearing the cusp of use for aggressive tumor treatment. To that end, we further highlight future prospects in focus as researchers continue developing more optimal vehicles for the delivery of therapeutic cargo.

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Conjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand Functionalization

et al. 2019

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Two‐step functionalization of 4‐diphenylphosphino benzoic acid with biotin afforded 2‐(biotinyloxy)ethyl 4‐(diphenylphosphanyl)benzoate (LP), that was subsequently used to synthesize the Ru(II) arene complexes [RuCl2(η6‐p‐cymene)(LP)] (1), [Ru(C2O4)(η6‐p‐cymene)(LP)] (2) and [Ru(curc)(η6‐p‐cymene)(LP)]NO3 ([3]NO3), the latter incorporating curcumin (curcH) as an additional bioactive fragment. [Ru(curc)(η6‐p‐cymene)(PPh3)]NO3 ([4]NO3) was also prepared as a reference compound. Compounds 2 and [3]NO3 exhibited excellent stability in water/DMSO solution while being slowly activated in the cell culture medium over 72 hours. Together with LP, they were therefore assessed for their antiproliferative activity towards a panel of cancer cell lines, with different levels of biotin transporter expression. The apparent affinity of the compounds towards avidin varies, and their antiproliferative activity does not correlate with biotin transporter expression, although it is systematically enhanced when biotin‐free cell culture medium is used.

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Cellular uptake of glucoheptoamidated poly(amidoamine) PAMAM G3 dendrimer with amide-conjugated biotin, a potential carrier of anticancer drugs

Cited by 29 publications

References 32 publications

Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates

Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates

<p>PAMAM Dendrimer Nanomolecules Utilized as Drug Delivery Systems for Potential Treatment of Glioblastoma: A Systematic Review</p>

Conjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand Functionalization

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