Comprehensive review of Pluronic® polymers of different shapes with prominent applications in photodynamic therapy

Abstract

In this review, we have highlighted different types of Pluronic® polymers for prominent photodynamic therapy (PDT) applications. To begin with, we have provided the definition and mechanism of PDT and enumerate its advantages over other frequently used therapeutic modalities. We have also presented a detailed explanation of the structure and properties of Pluronic® polymers. After successfully introducing both PDT and Pluronic® materials, we have provided a detailed discussion of the different types of Pluronics® available, based on their shape, size, and morphologies. The dependence of the properties of the Pluronics® on temperature and morphology has also been elaborated, which is essential for understanding the applicability of Pluronics® in the field of biomedicine. Next, the mechanism of PDT has been illustrated in detail, which is followed by an expanded analysis of the requisite properties of photosensitizers (PS) for efficient PDT, including discussions on the triplet excited-state lifetimes of the PSs, facile intersystem crossing (ISC), and other excited-state properties. Thus, we have provided a detailed discussion on the morphological effects on the physicochemical properties in this review.

Introduction

Photodynamic therapy (PDT) has proved to be a remarkable technique in terms of biomedical applications. It involves the excitation of an organic chromophore, known as photosensitizer (PS), which can be elevated to its excited state by irradiating with light of a particular wavelength. The excited-state PS can undergo a series of reactions, generating highly reactive intermediates, i.e., reactive oxygen species (ROS) like hydroxyl radical (OH), singlet oxygen (¹O₂), and superoxide radical (O₂⁻), which in turn participate in many biological reactions. Since light is employed as the activating trigger, the PDT process is a non-invasive treatment modality with few undesired harmful effects, and has thus found widespread application in treating different types of solid tumors, multidrug-resistant (MDR) cancer cells, different types of microbes, etc. [1], [2], [3], [4] However, the PSs presently in use for PDT applications are hydrophobic in nature, which prevents their internalization and accumulation in cells. To circumvent this issue, researchers have been looking for better alternatives e.g., organic nanoparticles, semiconductor inorganic nanoparticles, polymeric nanoparticles, upconversion nanoparticles, etc. Among these, polymeric nanoparticles have gained prominence due to their biocompatibility, solubility, and multifunctional ability,[5] along with the inherent biological activities of some of the constituent polymers.[6] Such polymer-mediated treatment modalities are recognized as “Polymer Therapeutics”.

Various synthetic polymers, including micelles, hydrogels, and their conjugates with some biologically active cargo, are currently under clinical trial.[7] The most widely used synthetic polymers for biological applications include polyethylene glycol (PEG), poly(glutamic acid) (PGA), poly(lactic acid) (PLA), and poly(D,L-lactide-co-glycolide) (PLGA).[8], [9] Amphiphilic block copolymers have afforded the most inspiring results as PSs owing to their unique ability to form micellar structures. Such micelles can encapsulate different biologically active compounds and release them in a regulated manner at the specific point of interest under physiological conditions. Biologically important compounds captured within the micelle can thus be protected from any undesired interactions under physiological conditions, leading to minimized side effects.[10] In this context, amphiphilic triblock polymers, comprising polyoxypropylene (PPO) and polyoxyethylene (PEO) as the hydrophobic and hydrophilic units, have garnered considerable attention. These FDA-approved poloxamers are commercially known as Pluronic® and have been marketed by BASF.[11], [12] Apart from having excellent surfactant-like behavior, Pluronics® are superior to other amphiphilic polymers in terms of the following characteristics: i) noteworthy interaction with biofilms and other hydrophobic materials, ii) improved circulation time of the biologically important material by the hydrophilic part, thus preventing excretion via the reticulo-endothelial system, iii) enhancement of the phagocytosis process by the hydrophobic part, thus increasing the accumulation of otherwise hydrophobic drugs inside the target cell, and iv) the ability to deplete the ATP level and inhibit the regular functioning of the P-glycoproteins (P-gps), leading to efficient cancer cell annihilation.[11], [13], [14] Here, we have presented graphs (Scheme 1) highlighting works on Pluronic® for the last 20 years to emphasize its importance in biomedicine.

There have been some reports describing Pluronic®-based materials of different compositions, along with their intriguing physicochemical properties with vivid illustrations. There has also been some research on the applications of Pluronic®-based materials as drug delivery vehicles, biomarkers, and nanovehicles.[15], [16], [17], [18] However, to the best of our knowledge, there has been no extensive discussion on Pluronic® materials of different shapes and their applications in PDT as a cancer treatment modality. This review is aimed at summarizing the ongoing studies on Pluronics® applied in the field of cancer treatment via PDT in a single publication (Fig. 1). Fig. 1 depicts different morphologies of Pluronics® e.g., lamellar, hexagonal, gel-type, dendrimer, and mixed Pluronic®. The following Fig. 1 also presents a schematic mechanistic pathway for PDT, which involves excitation of a photosensitizer (PS) from its ground state (¹PS) to singlet excited state (¹PS*). From, the singlet excited state, the PS can undergo intersystem crossing to reach its triplet excite state (³PS*), wherefrom it can dissipate its excess energy to ground state triplet molecular oxygen (³O₂) leading to the formation of reactive oxygen species like singlet oxygen (¹O₂), known as the Type II PDT. Further, the excited PS can directly interact with cellular substrates to result in reactive free radical intermediates, which is the Type I PDT. In the present article, the different forms of Pluronics® presently being utilized for PDT are discussed in detail along with their influence on better accumulation and enhanced PDT properties of classical hydrophobic PSs. The spatio-temporal control over PDT activities is also depicted.