New Advances in Biomedical Application of Polymeric Micelles

Abstract

In the last decade, nanomedicine has arisen as an emergent area of medicine, which studies nanometric systems, namely polymeric micelles (PMs), that increase the solubility and the stability of the encapsulated drugs. Furthermore, their application in dermal drug delivery is also relevant. PMs present unique characteristics because of their unique core-shell architecture. They are colloidal dispersions of amphiphilic compounds, which self-assemble in an aqueous medium, giving a structure-type core-shell, with a hydrophobic core (that can encapsulate hydrophobic drugs), and a hydrophilic shell, which works as a stabilizing agent. These features offer PMs adequate steric protection and determine their hydrophilicity, charge, length, and surface density properties. Furthermore, due to their small size, PMs can be absorbed by the intestinal mucosa with the drug, and they transport the drug in the bloodstream until the therapeutic target. Moreover, PMs improve the pharmacokinetic profile of the encapsulated drug, present high load capacity, and are synthesized by a reproducible, easy, and low-cost method. In silico approaches have been explored to improve the physicochemical properties of PMs. Based on this, a computer-aided strategy was developed and validated to enable the delivery of poorly soluble drugs and established critical physicochemical parameters to maximize drug loading, formulation stability, and tumor exposure. Poly(2-oxazoline) (POx)-based PMs display unprecedented high loading concerning water-insoluble drugs and over 60 drugs have been incorporated in POx PMs. Among various stimuli, pH and temperature are the most widely studied for enhanced drug release at the site of action. Researchers are focusing on dual (pH and temperature) responsive PMs for controlled and improved drug release at the site of action. These dual responsive systems are mainly evaluated for cancer therapy as certain malignancies can cause a slight increase in temperature and a decrease in the extracellular pH around the tumor site. This review is a compilation of updated therapeutic applications of PMs, such as PMs that are based on Pluronics^®, micelleplexes and Pox-based PMs in several biomedical applications.

Keywords: biomedical applications; cancer-target delivery; copolymers; nanocarrier; polymeric micelles; theranostic.

Figure 1

Schematic illustration of the main topics addressed in the Reflection Paper of the European Medicines Agency (EMA) regarding the “Development of block-copolymer-micelle medicinal products”. Reprinted from [16] under a CC-BY 4.0 license.

Figure 2

The evolution of the structure of block copolymers. Some advantages of the use of polymeric micelles and supramolecular structures.

Figure 3

Examples of the application of Poly(2-oxazoline) (POx)-based polymeric micelles and the assessment of their pharmacokinetics (PK) and bioequivalence profiles. In (A) poly(2-methyl-2-oxazoline-block-2-butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx) is used with an alkylated cisplatin prodrug to enable co-formulation of etoposide (ETO) and platinum drug combination (“EP/PE”) in a single high-capacity vehicle to improve the treatment of small cell lung cancer (SCLC). The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. Reprinted with permission from [58]. Copyright 2018 American Chemical Society. In (B) a three-compartmental model describing the PMs drug delivery to a tumor. The drug is administered as bolus in the form of PMs (1) and is subsequently distributed between the serum (2) and tumor (3) compartments. The PK constants correspond to: k₁₂—rate of drug transfer from PMs to serum; k₂₁—rate of drug re-capture from serum to PMs; k₁₃—rate of transfer (permeability) of the micellar drug to tumor; k₂₃—rate of transfer of the serum-bound drug to tumor; k₃₁ and k₃₂—rates of drug reabsorption from tumor to PMs and serum, respectively; and k₁₀ and k₂₀—micellar and serum-bound drug clearances, respectively. The model assumes that the drug solubility in blood is very low and the free drug form in the blood is, therefore, neglected. Reprinted from [59], Copyright 2018, with permission from Elsevier. In (C) a comprehensive preclinical assessment of the poly (2-oxazoline)-based polymeric micelle of paclitaxel (PTX) (POXOL hl-PMs), including bioequivalence comparison to the clinically-approved paclitaxel nanomedicine, Abraxane^®. Reprinted from [67], Copyright 2018, with permission from Elsevier.

Figure 4

Glycosylated-PEGylation of anti-PD-L1 antibodies for creating a targeted immunotherapy against glioblastoma. The glycosylated-PEGylation allowed the active transport of the antibody through the BBTB of glioblastoma by targeting the GLUT1 on the endothelial cells. Inside the tumor, the antibodies were dePEGylated by the cleavage of the reduction-sensitive bonds. In off-target tissues, the coated antibodies remained silent, avoiding the immune-related adverse events. Reprinted with permission from reference [76]. Copyright Nature 2021.

Figure 5

Structures of poloxamers/Pluronics^® and poloxamines/Tetronics^®.

Figure 6

Routes of internalization and interactions of Pluronic^®-like polymeric micelles and cancer cells.

Figure 7

Examples of Pluronic^®-based approaches for nanotheranostics. In (A), it schematically represents the development of Pluronic^® F127 stabilized conjugated polymer nanoparticles for Near Infra-Red (NIR) fluorescence imaging and dual phototherapy applications. Reprinted from [130] Copyright 2021, with permission from Elsevier. In (B), is a representative scheme of the formulation of folate-targeted Pluronic^® F127-chitosan nanocapsules that are loaded with Infra-Red (IR)780 for near-infrared fluorescence imaging and photothermal-photodynamic therapy of ovarian cancer. Reprinted from [131] Copyright 2021, with permission from Elsevier. In (C), it represents a schematic overview of the polyphenol–Pluronic^® self-assembled supramolecular nanoparticles (PPNPs) for tumor NIR fluorescence/Positron Electron Transmission (PET) imaging. Particularly, in (C, a) it represents the chemical structure of Pluronic^® F127, TA and IR780. In (C, b) a schematic illustration of the synthesis of PPNPs-IR780-⁸⁹Zr. The polyphenols in Tannic Acid (TA) have strong hydrogen bonding with the PEO chain in F127. IR780 was loaded by hydrophobic interaction with Polypropylene oxide (PPO) chain in F127. ⁸⁹Zr was chelated by excess phenol groups in TA. Reprinted from [129] Copyright 2021, with permission from Elsevier.

Figure 8

Schematic representation of the comparison between conventional topical marketed formulations and formulations containing polymeric micelles as drug carriers, and the results that were obtained.

Figure 9

Schematic view of the skin layers and skin penetration routes. Reprinted from [139] under a CC BY license.

Figure 10

Basic structure and summary of the properties of micelleplexes as well as their therapeutic application in ovarian cancer, liver cancer, and glioma.