Synthesis of New Macromolecules for Application in Biological and Medicinal Chemistry

Abstract

This chapter reviews the recent progress in the design and use of self-assembled polymeric nanostructures, focusing on their applications in enzyme mimicking catalysis and photodynamic therapy. The first part discusses how advanced polymerisation techniques, including ring opening polymerisation, reversible addition fragmentation chain transfer, and atom transfer radical polymerisation, allow precise control over polymer composition, chain length, and functionality. These methods are important for forming amphiphilic block copolymers that can self-assemble into nanostructures such as micelles, vesicles, and polyion complex. The second section describes the dendrimers, which are well defined and highly branched macromolecules that can be formed through a step by step synthetic methods that allows accurate control over molecular size and surface functionality. Their internal cavities and surface groups make them useful for encapsulating photosensitisers and delivering them to tumour tissues for targeting. The third part focuses on porphyrins, which are conjugated macrocyclic compounds with a central metal binding site and versatile chemical modification possibilities. Their encapsulation into the micelle, polyion complex, and dendrimer structures improves their solubility, stability, and functional performance in enzyme mimicking catalysis and as photosensitiser drug photodynamic therapy. In short, this review summarises how the combination of controlled polymerisation, precise molecular design, and porphyrin chemistry leads to multifunctional materials. These systems have the potential for use in catalysis, oxygen delivery, and light-activated cancer therapy, providing a strong foundation for further research in multifunctional polymeric systems.

Enzymes are the most efficient catalysis that nature provides; they have the potential to accelerate a biochemical reaction under mild conditions (e.g., neutral pH 7.4 phosphate buffer, ambient temperature, and aqueous medium) with high catalytic efficiency mimicking the physiological environment of natural enzyme. For instance, the natural enzyme cytochrome P-450, which is classified as monooxygenases that contain a metalloporphyrin active site confined within a pocket formed by surrounding protein structure. This confined environment known for its ability to enhance the efficiency and selectivity of enzymatic reactions that occur in water under mild conditions. These processes, which are precisely controlled by enzymes due to their well-organised active sites, three-dimensional structures and capability to operate in aqueous environments, have inspired the development of a synthetic enzyme model for use in catalysis. However, the development of straightforward biomimetic synthetic systems with excellent catalytic performance similar to natural enzymes has significant challenges. Hence, supramolecular chemistry strategies are being used to mimic enzymes, which leads to diverse approaches to achieving enzyme-like efficiency. Herein, we aimed to develop an amphiphilic diblock copolymer that is capable of self-assembling into micelles in an aqueous environment at pH 7.4 of phosphate buffer solution before introducing a porphyrin terminated polyethylene glycol (PEG) as an active site specifically, a tetraphenyl porphyrin-PEG with an iron (Fe) ion encased within its cavity to form a co-micelle nanoreactor. The oxidation of iron(III) methoxy polyethylene glycol-4-(10, 15, 20-triphenylporphyrin-5-yl)-benzoic acid amide (mPEG-Fe-MCTPP) was examined using meta-chloroperoxybenzoic acid (m-CPBA) as an oxidant in the absence and presence of Methoxy Poly(ethylene glycol) methyl ether45-block-poly-(Ɛ-poly caprolactone)28 ( mPEG45-PCL28) as a micelle control system. The mPEG45-PCL28 was used as a control to examine the influence of the micelle system on the rate of mPEG-Fe-MCTPP oxidation. A series of experiments with different ratio of micelle to porphyrin were conducted, using a concentration of 1 mg/mL of mPEG45-PCL28 and 0.5 mg/mL and varying porphyrin concentrations of 0.5 mg/mL, 0.25 mg/mL, and 0.125 mg/mL respectively, in the presence of 1.73 mg/mL of m-CPBA as an oxidant. The obtained results confirmed the essentiality of using a micelle system that can control the position of the metalloporphyrin catalyst and inhibit its aggregation. For example, the mPEG-Fe-MCTPP exhibited a higher oxidation rate as porphyrin concentration increased from 0.003 M s-1 to 0.006 M s-1 at 0.125 mg/mL, from 0.01 M s-1 to 0.03 M s-1 at 0.25 mg/mL, and from 0.02 M s-1 to 0.04 M s-1 at 0.5 mg/mL in the presence of the micelle system. This demonstrates that the micelle system enhances oxidation efficiency by providing a confined environment for the reactants within the comicelle system, thereby increasing the overall reaction rate.

Photodynamic therapy (PDT) is very effective clinical treatment for different conditions, including cancer, and certain eye and skin conditions. It works by the activation of a photosensitiser molecule with specific wavelengths of light, resulting in the production of singlet oxygen (1O2) from molecular oxygen that kill cancer tissues. As most of photosensitiser molecules s are hydrophobic, they resist intravenous administration, and show very low selectivity. As such, high doses are given, which results in the active species attacking healthy tissues. Herein, we report the use of nano water-soluble delivery system, that can encapsulate the poorly soluble photosensitizer within their internal hydrophobic environments and deliver oxygen to targeted tumour tissues. This new nano delivery system can self-assemble into polyion complex (PIC) micelles with a diameter of around 100 to 800 nm. As well as encapsulation, delivery systems with these sizes can accumulate selectively within tumours, via the enhanced permeability and retention effect. As such, optimal doses will be required, limiting the toxic side effects described above. These effective nanocarriers and encapsulation agents are used in various medicinal applications, such as delivering drugs in PDT treatments.

The interest in effective drug delivery techniques that precisely target tumour tissues without causing serious side effects has grown in conjunction with the identification of new, bioavailable pharmaceutical components. Toward this end, a number of macromolecules have been engineered as drug delivery systems, including those used in photodynamic therapy (PDT). However, several factors can influence the success of PDT, including the poor solubility of many anticancer drugs as well as site-specific delivery. To overcome these issues, a series of neutral PAMAM-OH dendrimer generations ranging from G 0.5 to G 3.5 were synthesised through the convergent method. The hydrophobic photosensitisers tetraphenylporphyrin and zinc-tetraphenyl porphyrin were then encapsulated. The results showed that the PAMAM-OH dendrimers were capable of improving the solubility of free-base porphyrin and metalated porphyrin. The findings also revealed that the zinc porphyrin could be encapsulated significantly more than the free-base porphyrin. This enhancement was attributed to the ability of the zinc porphyrin to coordinate to internal amines within a neutral PAMAM dendrimer.