Dexamethasone – PAMAM dendrimer conjugates for retinal delivery: preparation, characterization and <i>in vivo</i> evaluation

Yavuz, Burçin; Pehlivan, Sibel Bozdağ; Bolu, Burcu Sumer; Sanyal, Rana; Vural, İmran; Ünlü, Nurşen

doi:10.1111/jphp.12587

Cited by 48 publications

(45 citation statements)

References 36 publications

(38 reference statements)

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“…The spectrum of PSPD shows that the signals at δ 2.0 ppm are associated with the methyl protons of DMMA (Figure S3, Supporting Information) . In the P 123 ‐Dex 1 H NMR spectrum (Figure S4, Supporting Information), Dex signals could be better visualized in the 5.0–8.0 ppm range . The above results suggested that the proposed structure was synthesized successfully.…”

Section: Resultsmentioning

confidence: 80%

A Cooperative Dimensional Strategy for Enhanced Nucleus‐Targeted Delivery of Anticancer Drugs

Wang

Bai

et al. 2017

Adv Funct Materials

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Although previous efforts have focused on altering the size of drug delivery carriers with the goal of improving the efficacy of anticancer therapy, the penetration of nuclear pores still represents a formidable barrier for the existing drug delivery systems. To this end, a cooperative, dimensional strategy is employed that can considerably improve intranuclear drug delivery to augment the overall therapeutic efficacy of therapeutics requiring nuclear entry. This cooperative strategy relies on i) the pH and redox responsiveness of micelles (termed PSPD) to extend blood circulation and increase both the cellular uptake and the redox sensitivity of PSPD to reduce micelles to a size that is more capable of nuclear entry and ii) a dexamethasone-conjugated micelle (termed Dex-P 123 ) to target nuclei and dilate nuclear pores to allow PSPD to freely penetrate the nuclear pores. The resulting hybrid micelles, termed PSPD/Dex-P 123 , are found to deliver doxorubicin into cell nuclei more efficiently, thereby inducing more pronounced cytotoxicity against cancer cells in vitro. Importantly, a much more effective inhibition of tumor growth is observed in tumor-bearing mice, demonstrating the feasibility of this cooperative strategy for in vivo applications. The current study defines a useful dimensional strategy to improve nuclear-targeted and intranuclear drug delivery.

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Section: Resultsmentioning

confidence: 80%

A Cooperative Dimensional Strategy for Enhanced Nucleus‐Targeted Delivery of Anticancer Drugs

Wang

Bai

et al. 2017

Adv Funct Materials

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“…Studies involving anionic PAMAM species confirmed a similar toxic effect towards bacterial membranes, however at higher concentrations compared to their cationic counterparts [21,45]. Interestingly, there are only few studies on eukaryotic membranes assessing anionic PAMAM dendrimers, but all reports indicate no or little toxicity even at concentrations up to 1 mg mL -1 (human corneal epithelial cells; human glioma cells) [49,68]. The different interaction kinetics of PAMAM G5 and PAMAM G4.5 observed in our study indicate different modes of penetration into the DPPG and DPPC lipid monolayers, which might be related to the distinctive toxicity behaviour of both PAMAM species reported in some of the studies mentioned above, and might be due to the lipid model used..…”

Section: Discussionmentioning

confidence: 92%

“…Interestingly, fewer studies have been carried out using anionic dendrimers despite their lower cytotoxicity [25,44], antimicrobial activity [21,45] and suitability as potential drug delivery agents [46,47]. Just recently, their advantages over the cationic counterparts have started to attract more interest in the research community and membrane interactions in vitro were studied with the view of their potential as an anionic drug carrier [48,49]. However, the molecular processes underlying their interactions with biomembranes and their lower cytotoxicity are still not understood and very few studies have been focussing on elucidating anionic PAMAM's interaction mechanism with model lipid membranes [50,51] or proteins [52,53] so far.…”

Section: Discussionmentioning

confidence: 99%

Biophysical studies in polymer therapeutics: the interactions of anionic and cationic PAMAM dendrimers with lipid monolayers

Wilde

Green

Sanders

et al. 2017

Journal of Drug Targeting

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Understanding how polymers interact with biological membranes is important for the development of polymer-based therapeutics and wider biomedical applications. Here, biophysical methods (surface pressure measurements, external reflection FTIR) have been used to investigate the interaction between PAMAM dendrimers (Generation 5 or 4.5) and anionic (DPPG) or zwitterionic (DPPC) model membranes. We observed a concentration-dependent binding behaviour of both PAMAM species to both model membranes; however, equivalent levels of penetration into DPPC monolayers required approximately 10-fold higher dendrimer concentrations than for penetration into DPPG monolayers. Overall, the anionic PAMAM G4.5 showed a slightly better penetration ability which could be caused by repulsive forces towards the lipid layers. In comparison, increasing concentration of cationic PAMAM G5 leads to saturation of adsorption at the anionic lipid surface before penetration into the lipid layer likely driven by electrostatic attraction. Our studies also showed that physiologically relevant concentrations of sodium chloride (144 mM) decreased PAMAM penetration into DPPG monolayers but did not significantly affect the dendrimer-DPPC interaction. These results provide an insight into the mechanism of interaction between charged dendritic polymers with a lipid interface and show that the nature of such interactions are affected by lipid headgroup, dendrimer charge and solution salinity.

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“…So far, they are still being tested at the in vitro stage for inhibition of VEGF expression with intravitreally administered antisense oligonucleotide compounds. [292][293][294][295][296] Novel ocular injection devices, such as the iTrack microcatheter (iScience Interventional), allow the administration of various medications in the suprachoroidal space to allow for a sequestered, sustained release of drug. Recently, a combination of bevacizumab and triamcinolone was delivered via the iTrack device to the submacular area in a pilot study of patients with chronic ME and HEs.…”

Section: Drug Delivery Strategiesmentioning

confidence: 99%

<p>The Evolving Treatment of Diabetic Retinopathy</p>

Mansour¹,

Browning²,

Wong³

et al. 2020

OPTH

162

119

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Purpose: To review the current therapeutic options for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) and examine the evidence for integration of laser and pharmacotherapy. Methods: A review of the PubMed database was performed using the search terms diabetic retinopathy, diabetic macular edema, neovascularization, laser photocoagulation, intravitreal injection, vascular endothelial growth factor (VEGF), vitrectomy, pars plana vitreous surgery, antiangiogenic therapy. With additional cross-referencing, this yielded 835 publications of which 301 were selected based on content and relevance. Results: Many recent studies have evaluated the pharmacological, laser and surgical therapeutic strategies for the treatment and prevention of DR and DME. Several newer diagnostic systems such as optical coherence tomography (OCT), microperimetry, and multifocal electroretinography (mfERG) are also assisting in further refinements in the staging and classification of DR and DME. Pharmacological therapies for both DR and DME include both systemic and ocular agents. Systemic agents that promote intensive glycemic control, control of dyslipidemia and antagonists of the renin-angiotensin system demonstrate beneficial effects for both DR and DME. Ocular therapies include anti-VEGF agents, corticosteroids and nonsteroidal anti-inflammatory drugs. Laser therapy, both as panretinal and focal or grid applications continue to be employed in management of DR and DME. Refinements in laser devices have yielded more tissue-sparing (subthreshold) modes in which many of the benefits of conventional continuous wave (CW) lasers can be obtained without the adverse side effects. Recent attempts to lessen the burden of anti-VEGF injections by integrating laser therapy have met with mixed results. Increasingly, vitreoretinal surgical techniques are employed for less advanced stages of DR and DME. The development and use of smaller gauge instrumentation and advanced anesthesia agents have been associated with a trend toward earlier surgical intervention for diabetic retinopathy. Several novel drug delivery strategies are currently being examined with the goal of decreasing the therapeutic burden of monthly intravitreal injections. These fall into one of the five categories: non-biodegradable polymeric drug delivery systems, biodegradable polymeric drug delivery systems, nanoparticle-based drug delivery systems, ocular injection devices and with sustained release refillable devices. At present, there remains no one single strategy for the management of the particular stages of DR and DME as there are many options that have not been rigorously tested through large, randomized, controlled clinical trials. Conclusion: Pharmacotherapy, both ocular and systemic, will be the primary mode of intervention in the management of DR and DME in many cases when cost and treatment burden are less constrained. Conventional laser therapy has become a secondary intervention in these instances, but remains a first-line option when cost and ...

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Dexamethasone – PAMAM dendrimer conjugates for retinal delivery: preparation, characterization and in vivo evaluation

Abstract: Current studies are focused on formulation improvement to enhance hydrolysis and clearance time.

Cited by 48 publications

References 36 publications

A Cooperative Dimensional Strategy for Enhanced Nucleus‐Targeted Delivery of Anticancer Drugs

A Cooperative Dimensional Strategy for Enhanced Nucleus‐Targeted Delivery of Anticancer Drugs

Biophysical studies in polymer therapeutics: the interactions of anionic and cationic PAMAM dendrimers with lipid monolayers

<p>The Evolving Treatment of Diabetic Retinopathy</p>

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