الفهرس 
Chapter 1: IntroductionOnly 14 pages are availabe for public view
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Abstract
Polyethylene glycols (PEGs) are hydrophilic polymers that are abundantly used in various pharmaceutical applications, in the food industry, cosmetics, and other daily used household products. In PEGylated therapeutics, the binding of PEG to nanocarriers or drug molecules is built. PEGylated therapeutics are usually employed to enhance the pharmacokinetics and the therapeutic efficacy of drugs. However, despite the promising features and widespread applications of PEG, PEG immunogenicity and antigenicity are a challenge. Anti-PEG antibodies (Abs) were widely reported after the administration of many PEGylated products. Furthermore, anti-PEG Abs were also reported in normal populations with no previous treatments with PEGylated products. Both treatment-induced and/or pre-existing anti-PEG Abs are reported to compromise the pharmacokinetics and therapeutic efficacy of PEGylated products through what is commonly known as the accelerated blood clearance phenomenon (ABC phenomenon). The exact source of the naturally occurring anti-PEG Abs remains unclear. However, some researchers assumed that the daily uses of many products that contain PEG or/and PEG derivatives have a considerable role in the incidence of these Abs. The aims of my thesis, therefore, were to study the role of the daily used PEG derivatives including cosmetics on the induction of the anti-PEG Abs in a mouse model. In addition, the mechanism of the induction of such Abs was studied. Results showed that the topical application of PEG derivatives in cosmetics induced anti-PEG Abs that lasted in blood circulation for up to two months. This type of cosmetic product secretes Abs in a T cell-deficient mouse model through the thymus-independent (TI) pathway. The marginal zone (MZ) B cells play a vital role in anti-PEG Abs production. It was found that the depletion of (MZ) B cells by cyclophosphamide (CYP) diminished the induction of such Abs. Also, splenectomy markedly attenuated the blood levels of Abs induced by topical cosmetics.
In this study, the impact of the anti-PEG Abs, produced in response to topical cosmetics, on the blood clearance and therapeutic efficacy of antitumor PEGylated nanocarriers (liposomal formulations) was investigated in BALB/c mice. Results revealed that the circulating anti-PEG Abs induced enhanced blood clearance of Doxil® (Doxorubicin-loaded PEGylated liposomal formulation) and oxaliplatin-loaded PEGylated liposomes (liposomal l-OHP). The blood concentrations of either doxorubicin or oxaliplatin were significantly lower in mice with anti-PEG Abs compared with the naïve mice. Furthermore, the tumor growth inhibitory effect of both drugs was significantly attenuated in mice with anti-PEG Abs. The mice that received the same treatment in the absence of these Abs showed higher tumor growth inhibitory effects.
The impact of the topically applied cosmetical products that contain PEG and/or PEG derivatives on the pharmacokinetic parameters and pharmacological activity of PEGylated proteins was investigated in a BALB/c mouse model. Results showed compromised pharmacokinetics with rapid blood clearance of both subcutaneously (SC) and intravenously (IV) injected PEG-G-CSF (PEGylated form of G-CSF which is a granulocyte colony-stimulating growth factor). Moreover, in mice with neutropenia, the pharmacological activity of both IV and SC-administered PEG-G-CSF was markedly suppressed in mice pretreated with PEG-containing cosmetic products.
In conclusion, this study confirmed the major role of the daily used PEG and/or PEG derivative/s present in numerous cosmetical products on the prevalence of the pre-existing naturally occurring anti-PEG Abs. These anti-PEG Abs hardly compromised the pharmacokinetic parameters of the administered PEGylated liposomal formulations and PEGylated proteins through the ABC phenomenon. Therefore, the therapeutic efficacy of both PEGylated liposomal formulations and PEGylated proteins was significantly attenuated when administered in the presence of these Abs in a mouse model.