Therapeutic efficacy and gastrointestinal biodistribution of polycationic nanoparticles for oral camptothecin delivery in early and late-stage colorectal tumor-bearing animal model

Ünal, Sedat; Öztürk, Süleyman Can; Bilgiç, Elif; Yanık, Hamdullah; Korkusuz, Petek; Aktaş, Yeşim; Benito, Juan M.; Esendağlı, Güneş; Bilensoy, Erem

doi:10.1016/j.ejpb.2021.10.010

Cited by 16 publications

(16 citation statements)

References 58 publications

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“…However, each brings its own advantages and disadvantages, and an effective formulation for colon carcinomas has not been developed yet. From this point of view, novel drug delivery systems and nanoparticular drug delivery systems are considered and evaluated as trends and promising approaches in the treatment of colon carcinomas as well as of many other diseases [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…While it protects the drug from various destructive effects of GIT with its polymeric protective structure, with the help of some modifications such as surface modifications, it allows the nanoformulation to exhibit locally higher concentrations in the colon [13,14,[16][17][18]. Physiologically specific factors in the tumor microenvironment, such as increased negatively charged mucin, decreased pH value, and increased temperature, may provide design clues for mucoadhesive polymeric nanoparticles that have a potential to exhibit higher drug release or help to alleviate colorectal tumor in colon region [11,19,20].…”

Section: Introductionmentioning

confidence: 99%

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Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics

Ünal¹,

Doğan²,

Aktaş³

2022

Beilstein J. Nanotechnol.

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Intestinal cancers are the third most lethal cancers globally, beginning as polyps in the intestine and spreading with a severe metastatic tendency. Chemotherapeutic drugs used in the treatment of intestinal tumors are usually formulated for parenteral administration due to poor solubility and bioavailability problems. Pharmaceutically, clinical failure due to a drug’s wide biodistribution and non-selective toxicity is one of the major challenges of chemotherapy. In addition, parenteral drug administration in chronic diseases that require long-term drug use, such as intestinal tumors, is challenging in terms of patient compliance and poses a burden in terms of health economy. Especially in the field of chemotherapy research, oral chemotherapy is a subject that has been intensively researched in recent years, and developments in this field will provide serious breakthroughs both scientifically and socially. Development of orally applicable nanodrug formulations that can act against diseases seen in the distant region of the gastrointestinal tract (GIT), such as intestinal tumor, brings with it a series of difficulties depending on the drug and/or GIT physiology. The aim of this study is to develop an oral nanoparticle drug delivery system loaded with docetaxel (DCX) as an anticancer drug, using poly(lactic-co-glycolic acid) (PLGA) as nanoparticle material, and modified with chitosan (CS) to gain mucoadhesive properties. In this context, an innovative nanoparticle formulation that can protect orally administered DCX from GIT conditions and deliver the drug to the intestinal tumoral region by accumulating in mucus has been designed. For this purpose, DCX-PLGA nanoparticles (NPs) and CS/DCX-PLGA NPs were prepared, and their in vitro characteristics were elucidated. Nanoparticles around 250–300 nm were obtained. DCX-PLGA NPs had positive surface charge with CS coating. The formulations have the potential to deliver the encapsulated drug to the bowel according to the in vitro release studies in three different simulated GIT fluids for approximately 72 h. Mucin interaction and penetration into the artificial mucus layer were also investigated in detail, and the mucoadhesive and mucus-penetration characteristics of the formulations were examined. Furthermore, in vitro release kinetic studies of the NPs were elucidated. DCX-PLGA NPs were found to be compatible with the Weibull model, and CS/DCX-PLGA NPs were found to be compatible with the Peppas–Sahlin model. Within the scope of in vitro cytotoxicity studies, the drug-loaded NPs showed significantly higher cytotoxicity than a DCX solution on the HT-29 colon cell line, and CS/DCX-PLGA showed the highest cytotoxicity (p < 0.05). According to the permeability studies on the Caco-2 cell line, the CS/DCX-PLGA formulation increased permeability by 383% compared to free DCX (p < 0.05). In the light of all results, CS/DCX-PLGA NPs can offer a promising and innovative approach as an oral anticancer drug-loaded nanoformulation for intestinal tumors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics

Ünal¹,

Doğan²,

Aktaş³

2022

Beilstein J. Nanotechnol.

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“…Permeability studies performed with the Caco-2 cell line revealed a 276% increase in drug permeability and significantly higher intestinal penetration with the cationic CD formulation. In our further research [ 8 ], it was also reported that the oral CPT-loaded poly-β-CD-C6 NPs showed antitumoral and antimetastatic effects in a colorectal tumor-bearing animal model.…”

Section: Resultsmentioning

confidence: 99%

“…Preliminary studies have evidenced p K a values in the 8.3 range for non-amphiphilic surrogates of these cationic CDs, supporting the cationic character of the resulting NPs [ 20 ]. We hypothesized that these polycationic CD NPs, which we designed in our previous studies, could protect the active and stable lactone form of encapsulated CPT due to their acidic chemical structure [ 8 – 9 11 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Insight into oral amphiphilic cyclodextrin nanoparticles for colorectal cancer: comprehensive mathematical model of drug release kinetic studies and antitumoral efficacy in 3D spheroid colon tumors

Ünal¹,

Varan²,

Benito³

et al. 2023

Beilstein J. Org. Chem.

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Colorectal cancer (CRC) is the third most diagnosed cancer type globally and ranks second in cancer-related deaths. With the current treatment possibilities, a definitive, safe, and effective treatment approach for CRC has not been presented yet. However, new drug delivery systems show promise in this field. Amphiphilic cyclodextrin-based nanocarriers are innovative and interesting formulation approaches for targeting the colon through oral administration. In our previous studies, oral chemotherapy for colon tumors was aimed and promising results were obtained with formulation development studies, mucin interaction, mucus penetration, cytotoxicity, and permeability in 2D cell culture, and furthermore in vivo antitumoral and antimetastatic efficacy in early and late-stage colon cancer models and biodistribution after single dose oral administration. This study was carried out to further elucidate oral camptothecin (CPT)-loaded amphiphilic cyclodextrin nanoparticles for the local treatment of colorectal tumors in terms of their drug release behavior and efficacy in 3-dimensional tumor models to predict the in vivo efficacy of different nanocarriers. The main objective was to build a bridge between formulation development and in vitro phase and animal studies. In this context, CPT-loaded polycationic-β-cyclodextrin nanoparticles caused reduced cell viability in CT26 and HT29 colon carcinoma spheroid tumors of mice and human origin, respectively. In addition, the release profile, which is one of the critical quality parameters in new drug delivery systems, was investigated mathematically by release kinetic modeling for the first time. The overall findings indicated that the strategy of orally targeting anticancer drugs such as CPT with positively charged poly-β-CD-C6 nanoparticles to colon tumors for local and/or systemic efficacy is a promising approach.

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“…This study exemplifies that potency of CD in targeting cancer cells can be augmented with usage of suitable targeting agents. Another study involving polycationic β-CD complexed with camptothecin (CPT), a highly potent drug improved the stability of the drug for treatment of both early- and late-stage colon cancers ( Ünal et al, 2021 ). Several other studies show improved permeability, effective tumor site accumulation, and reduced non-specific toxicity ( Akkın et al, 2022 ; Zhang R. et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Cyclodextrin nanoparticles for diagnosis and potential cancer therapy: A systematic review

Karthic

Roy

Lakkakula

et al. 2022

Front. Cell Dev. Biol.

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Cancer is still one of the world’s deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost worldwide. Although chemotherapy is most widely used methodology to treat cancer, poor pharmacokinetic parameters of anticancer drugs render them less effective. Novel nano-drug delivery systems have the caliber to improve the solubility and biocompatibility of various such chemical compounds. In this regard, cyclodextrins (CD), a group of natural nano-oligosaccharide possessing unique physicochemical characteristics has been highly exploited for drug delivery and other pharmaceutical purposes. Their cup-like structure and amphiphilic nature allows better accumulation of drugs, improved solubility, and stability, whereas CDs supramolecular chemical compatibility renders it to be highly receptive to various kinds of functionalization. Therefore combining physical, chemical, and bio-engineering approaches at nanoscale to specifically target the tumor cells can help in maximizing the tumor damage without harming non-malignant cells. Numerous combinations of CD nanocomposites were developed over the years, which employed photodynamic, photothermal therapy, chemotherapy, and hyperthermia methods, particularly targeting cancer cells. In this review, we discuss the vivid roles of cyclodextrin nanocomposites developed for the treatment and theranostics of most important cancers to highlight its clinical significance and potential as a medical tool.

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Therapeutic efficacy and gastrointestinal biodistribution of polycationic nanoparticles for oral camptothecin delivery in early and late-stage colorectal tumor-bearing animal model

Cited by 16 publications

References 58 publications

Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics

Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics

Insight into oral amphiphilic cyclodextrin nanoparticles for colorectal cancer: comprehensive mathematical model of drug release kinetic studies and antitumoral efficacy in 3D spheroid colon tumors

Cyclodextrin nanoparticles for diagnosis and potential cancer therapy: A systematic review

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