Nazlı Erdoğar

Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles.

As nanomedicines are gaining momentum in the therapy of cancer, new biomaterials emerge as alternative platforms for the delivery of anticancer drugs with bioavailability problems. In this study, two novel amphiphilic cyclodextrins (FCD-1 and FCD-2) conjugated with folate group to enable active targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD-2 nanoparticles remained within the range of 70-275nm and 125-185nm, respectively. Zeta potential values were neutral and -20mV for FCD-1 and FCD-2 nanoparticles, respectively. Drug release studies showed initial burst release followed by a longer sustained release. Blank nanoparticles had no cytotoxicity against L929 cells. T-47D and ZR-75-1 human breast cancer cells with different levels of folate receptor expression were used to assess anti-cancer efficacy. Through targeting the folate receptor, these nanoparticles were efficiently engulfed by the breast cancer cells. Additionally, breast cancer cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate-dependent mechanism.

Cationic core-shell nanoparticles for intravesical chemotherapy in tumor-induced rat model: Safety and efficacy

Mitomycin C (MMC) has shown potent efficacy against a wide spectrum of cancers and is clinical first choice in superficial bladder tumors. However, intravesical chemotherapy with MMC has been ineffective due to periodical discharge of the bladder and instability of this drug in acidic pH, both resulting in high rate of tumor recurrence and insufficiency to prevent progression. Nanocarriers may be a promising alternative for prolonged, effective and safe intravesical drug delivery due to their favorable size, surface properties and optimum interaction with mucosal layer of the bladder wall. Hence, the aim of this study was to evaluate and optimize cationic core-shell nanoparticles formulations (based on chitosan (CS) and poly-ϵ-caprolactone (PCL)) in terms of antitumor efficacy after intravesical administration in bladder tumor induced rat model. Antitumor efficacy was determined through the parameters of survival rate and nanoparticle penetration into the bladder tissue. Safety of the formulations were evaluated by histopathological evaluation of bladder tissue as well as observation of animals treated with MMC bound to nanoparticles. Results indicated that chitosan coated poly-ϵ-caprolactone (CS-PCL) nanoparticles presented the longest survival rate among all treatment groups as evaluated by Kaplan-Meier plotting. Histopathological evaluation revealed that cationic nanoparticles were localized and accumulated in the bladder tissue. As intravesical chemotherapy is a local therapy, no MMC was quantified in blood after intravesical instillation indicating no systemic uptake for the drug which could have subsequently led to side effects. In conclusion, core-shell type cationic nanoparticles may be effective tools for the intravesical chemotherapy of recurrent bladder tumors.

Prolonged retention and in vivo evaluation of cationic nanoparticles loaded with Mitomycin C designed for intravesical chemotherapy of bladder tumours

To overcome the recurrence problem in bladder tumours; nanoparticles with positive surface charge may improve interaction with biological membranes for intravesical administration. The aim of this study was to design, develop and evaluate (in vitro–in vivo) cationic nanoparticles based on chitosan, poly-L-lysine or polycaprolactone for the effective intravesical delivery of chemotherapeutic agent MMC in a rat model. Poly-L-lysine-coated polycaprolactone nanoparticles and chitosan-coated polycaprolactone nanoparticles were prepared by the double emulsion technique. Chitosan nanoparticles were prepared by ionic gelation. It was found that nanoparticle formulations of 160–320 nm in size can be produced in 14–35% encapsulation efficiency. Variability in the particle size of nanoparticles depended on the preparation method. Encapsulation was increased by two-fold for CS–PCL as a result of the double emulsion technique. Commercial MMC product in solution form and cationic nanoparticle formulations were compared for in vivo bladder retention properties and effect of formulations on urine volume.

Amphiphilic cyclodextrin nanoparticles

Cyclodextrins are cyclic oligosaccharides obtained by enzymatic digestion of starch. The α-, β- and γ- cyclodextrins contain respectively 6, 7 and 8 glucopyranose units, with primary and secondary hydroxyl groups located on the narrow and wider rims of a truncated cone shape structure. Such structure is that of a hydrophobic inner cavity with a hydrophilic outer surface allowing to interact with a wide range of molecules like ions, protein and oligonucleotides to form inclusion complexes. Many cyclodextrin applications in the pharmaceutical area have been widely described in the literature due to their low toxicity and low immunogenicity. The most important is to increase the solubility of hydrophobic drugs in water. Chemically modified cyclodextrin derivatives have been synthesized to enhance their properties and more specifically their pharmacological activity. Among these, amphiphilic derivatives were designed to build organized molecular structures, through selfassembling systems or by incorporation in lipid membranes, expected to improve the vectorization in the organism of the drug-containing cyclodextrin cavities. These derivatives can form a variety of supramolecular structures such as micelles, vesicles and nanoparticles. The purpose of this review is to summarize applications of amphiphilic cyclodextrins in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important amphiphilic cyclodextrin applications in the design of novel delivery systems like nanoparticles.

Amphiphilic Cyclodextrin Derivatives for Targeted Drug Delivery to Tumors

Villiers has extensively studied cyclodextrins, a family of macrocyclic oligosaccharides linked by α-1,4 glycosidic bonds, in different fields since their discovery in 1891. The unique structure enabling inclusion complexation for natural cyclodextrins and cyclodextrin derivatives make them attractive for novel drug delivery systems. Cyclodextrins can be modified with long aliphatic chains to render an amphiphilic property and these different amphiphilic cyclodextrins are able to form nanoparticles without surfactants. In the literature, several different amphiphilic cyclodextrins are reported and applied to drug delivery and targeting especially to tumors. Specificly, folateconjugated amphiphilic cyclodextrin derivatives are used for active tumor targeting of poorly water soluble drugs and improve the efficacy and safety of therapeutic agents. On the other hand, effect of positive surface charge has also been under research in the recent years. Polycationic amphiphilic cyclodextrins have shown promise towards forming small complexes with negatively charged molecules such as drugs or plasmid DNA. Polycationic amphiphilic cyclodextrins enhance interaction with cell membrane due to their net positive surface charge. The scope of this review is to describe potential uses and pharmaceutical applications of tumor-targeted amphiphilic cyclodextrins, with focus on folate-conjugated cyclodextrin derivatives and polycationic cyclodextrin derivatives both studied by our group at Hacettepe University.

Therapeutic efficacy of folate receptor-targeted amphiphilic cyclodextrin nanoparticles as a novel vehicle for paclitaxel delivery in breast cancer

Abstract Purpose: The aim of this study is to test folate-conjugated cyclodextrin nanoparticles (FCD-1 and FCD-2) as a vehicle for reducing toxicity and increasing the antitumor efficacy of paclitaxel especially for metastatic breast cancer. Methods: For the evaluation of PCX-loaded FCD nanoparticles, animal studies were realised in terms of survival rate, tumour size, weight change, metastazis and histopathological examination. Results: FCD-1 displayed significant advantages such as efficient targeting of folate receptor positive breast cancer cells and having considerably lower toxicity compared to that of Cremophor®. When loaded with paclitaxel, FCD-1 nanoparticles, which have smaller particle size, neutral zeta potential, high encapsulation efficiency and better loading capacity for controlled release, emerged as an effective formulation in terms of cytotoxicity and high cellular uptake. In an experimental breast cancer model, anticancer activity of these nanoparticles were compatible with that of paclitaxel in Cremophor® however repeated administrations of FCD-1 nanoparticles were better tolerated by the animals. These nanoparticles were able to localise in tumour site. Both paclitaxel-loaded FCD-1 and FCD-2 significantly reduced tumour burden while FCD-1 significantly improved the survival. Conclusions: Folate-conjugated amphiphilic cyclodextrin nanoparticles can be considered as promising Cremophor®-free, low-toxicity and efficient active drug delivery systems for paclitaxel.

Cyclodextrin-Based Nanosystems in Targeted Cancer Therapy

Cancer is a disease that shows uncontrolled cell division and invasion in other tissues, resulting in high incidence and mortality worldwide. Classical chemotherapeutic agents have poor water solubility and lack of specificity, resulting in systemic toxicity and limitations of the maximum drug dose. Alternatively, the use of nanosized drug carriers overcomes these drawbacks and increase therapeutic efficacy of many chemotherapy drugs. Nanocarriers for drug delivery allows systems to combine properties for multiple functions. Here, cyclodextrins are of particular interest due to their good inclusion capability, excellent biocompatibility, and ability to self-assemble and form various stable nanoscale systems such as micellar aggregates, nanoreservoirs and nanoparticles for biomedical applications. These cyclodextrin-based nanosystems show several advantages in terms of stability, safety, the ability to encapsulate hydrophobic drugs and good in vivo tolerance.

Cyclodextrin-based polymeric nanosystems

Abstract Conventional drug delivery systems have been insufficient for treatment of several diseases especially cancer. Hydrophobic and hydrophilic polymeric nanoparticles have been developed for delivery of therapeutics such as drug or gene in order to overcome drawbacks of conventional therapy. Regardless, polymeric nanoparticles provide more effective treatment with reduced side effects of drugs. Cyclodextrins are more favorable natural polymers to prepare nano-sized drug delivery systems because of their physical and chemical properties. The other advantages of cyclodextrins are: to enhance bioavailability and stability of drug molecules, and protect them from physical conditions include pH, temperature and some enzymes. In order to overcome some disadvantages of natural cyclodextrins and enhance their solubility and interaction with biological membranes, amphiphilic cyclodextrins have been synthesized. These unique polymers have an ability to form nanoparticles in aqueous media, spontaneously. In this chapter, nanosystems based on natural and amphiphilic cyclodextrins will be described using examples from the literature. In addition, recent studies on cyclodextrin-based nano-sized drug delivery systems will be summarized. Our research group has carried out many studies and publications related to cyclodextrin nanoparticles with several drugs.

Chapter 19 – Cyclodextrin-based polymeric nanosystems

Abstract Conventional drug delivery systems have been insufficient for treatment of several diseases especially cancer. Hydrophobic and hydrophilic polymeric nanoparticles have been developed for delivery of therapeutics such as drug or gene in order to overcome drawbacks of conventional therapy. Regardless, polymeric nanoparticles provide more effective treatment with reduced side effects of drugs. Cyclodextrins are more favorable natural polymers to prepare nano-sized drug delivery systems because of their physical and chemical properties. The other advantages of cyclodextrins are: to enhance bioavailability and stability of drug molecules, and protect them from physical conditions include pH, temperature and some enzymes. In order to overcome some disadvantages of natural cyclodextrins and enhance their solubility and interaction with biological membranes, amphiphilic cyclodextrins have been synthesized. These unique polymers have an ability to form nanoparticles in aqueous media, spontaneously. In this chapter, nanosystems based on natural and amphiphilic cyclodextrins will be described using examples from the literature. In addition, recent studies on cyclodextrin-based nano-sized drug delivery systems will be summarized. Our research group has carried out many studies and publications related to cyclodextrin nanoparticles with several drugs.