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Thesis defences

PhD Oral Exam - Tarek Sabri, Chemistry

Albumin Conjugated Upconversion Nanoparticles for Photodynamic Therapy Applications

DATE & TIME
Tuesday, January 25, 2022 (all day)
COST

This event is free

ORGANIZATION

School of Graduate Studies

CONTACT

Dolly Grewal

WHERE

Online

When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.

Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.

Abstract

Photodynamic therapy (PDT) is the least invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cell. The procedure involves administration of photosensitizer, a light absorbing molecule, that upon irradiation by a specific wavelength will produce reactive singlet oxygen that induces cell death or tissue damage. Major limitations include poor selectivity of photosensitizers toward tumors, and radiation using visible light that weakly penetrates tissues. Hence, effectiveness of PDT is limited to superficial treatments, and its validity to treat deeper tissues is very limited.

Lanthanide upconverting nanoparticles (Ln-UCNP) are efficient energy transducers that can absorb light efficiently in the near infrared (NIR), while emitting via the process of upconversion in the UV-VIS-NIR regions of spectrum. NIR light excitation permits light penetration deeply in tissues, without causing any photodamage to biological entities. However, any foreign entity entering the body are coated by group of serum proteins (coronas). This will result in aggregation that might induce toxicity or change circulation fate of the nanoparticles lowering PDT efficacy. Albumin (ALB) the most abundant protein in serum, has been approved as a passive drug delivery loading modality. Herein, A modified version of desolvation method was developed to render Ln-UCNPs (NaGdF4: Yb3+, Er3+) dispersible in biological relevant media and biocompatible for PDT application. The approach generated a uniform ~2 nm thick shell with approximately 112 molecules of ALB were present to cover 15290 nm2 area of single NaGdF4: Yb3+, Er3+. Additionally, Rose Bengal (RB) photosensitizer was structurally modified, and energy transfer of different RB loaded on NaGdF4: Yb3+, Er3+ surface was studied under 980 nm irradiation. Further, in vitro studies using human alveolar lung cancer cells (A549) showed that RB presence solely allowed cellular internalization of ALB coated NaGdF4: Yb3+, Er3+. Also, cellular toxicity was induced under 980 nm excitation within a period of 10-minute exposure time.

New model of ALB conjugated to Ln-UCNPs is also developed. Bifunctional linker possessing maleimide group grafted on NaGdF4: Yb3+, Er3+ surface, and employed to target thiol group present on ALB cysteine 34. Albumin presence rendered Ln-UCNPs biocompatible and dispersible in aqueous environment and permitted the loading of different RB concentrations.

Spectrophotometric analysis of the RB photoreaction processes identified both type I & II energy transfer mechanism, through the release of hydroxyl radical (HO•) , and 1O2 respectively.

In vitro evaluation of the cellular activity of ALB presence on NaGdF4: Yb3+, Er3+ revealed a substantial selective cellular internalization effect using glioblastoma tumor cells (U251N), in comparison to A549 cells. Further, cellular toxicity assay of the nanoconstruct using U251N irradiated with 980 nm, revealed an intense cellular toxicity effect as a result of the enhanced cellular uptake, and the release of various toxic reactive oxygen radicals. Thus, RB modified ALB-NaGdF4: Yb3+, Er3+ provided biocompatible surface coating, targeting and cytotoxicity capabilities that all enhance PDT efficacy.

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