Perspective

Stability issues of polymeric micelles

This review aims to provide a systemic analysis of the in vivo, as well as subcellular, fate of polymeric micelles (PMs), starting from the entry of PMs into the body. Few PMs are able to cross the biological barriers intact and reach the circulation. In the blood, PMs demonstrate fairly good stability mainly owing to formation of protein corona despite controversial results reported by different groups. Although the exterior hydrophilic shells render PMs “long-circulating”, the biodistribution of PMs into the mononuclear phagocyte systems (MPS) is dominant as compared with non-MPS organs and tissues. Evidence emerges to support that the copolymer poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) is first broken down into pieces of PEG and PLA and then remnants to be eliminated from the body finally. At the cellular level, PMs tend to be internalized via endocytosis due to their particulate nature and disassembled and degraded within the cell. Recent findings on the effect of particle size, surface characteristics and shape are also reviewed. It is envisaged that unraveling the in vivo and subcellular fate sheds light on the performing mechanisms and gears up the clinical translation of PMs.

Nanotechnology has played a major contribution in developing different drug-loaded polymeric nanocarriers for therapeutic and diagnostic applications. Among the polymeric nanocarriers, the polymeric micelles have received much attention for the diagnosis and treatment of several complicated diseases. The polymers, which are amphiphilic in nature, are used to develop polymeric nanocarriers to overcome the solubility problems of lipophilic drugs. The size range of these polymeric micelles is 10 to 200 nm. This chapter provides a comprehensive overview of the structure and distinguishing features of polymeric micelles. It also gives insight about various polymers used in preparing polymeric micelles, different methods of preparation, and various types of polymeric nanocarriers. The applications and different factors effecting micelles have also been discussed here. Moreover, their limitations and prospects are been discussed.

Breast cancer stem cell (BCSC) properties are correlated with the malignancy of tumor cells. Sulforaphane (SFN), a natural isothiocyanate, has anti-cancer effects. However, SFN is an oil-like, hydrophobic and unstable substance. To enhance the inhibitory effect of SFN on BCSC-like properties, the mineralized hyaluronic acid-SS-tetradecyl nano-carriers (M-HA-SS-TA) were prepared. The nano-carriers possessed high SFN entrapment rate (92.36%) and drug-loading efficiency (33.64%). The carriers were responsive to the high reducing and mild acidic tumor micro-environment, leading to rapid SFN releasing from SFN-loaded nano-drug (SFN/M-HA-SS-TA). Through the specific recognition of breast cancer cells bearing CD44⁺ by HA, M-HA-SS-TA nano-carriers showed excellent tumor-targeting ability. Moreover, compared with free SFN, SFN/M-HA-SS-TA showed much stronger inhibition on the BCSC-like properties (invasiveness, self-renewal and tumor growth) both in vitro and in vivo. Together, these results suggested M-HA-SS-TA nano-carriers were promising platforms for tumor-targeted delivery of SFN, enhancing the therapeutic efficacy against BCSC-like properties by SFN.

The stability of self-assembled drug nanocarriers during blood circulation and the controlled intracellular drug delivery are two challenges in cancer therapy. In this paper, we constructed an adenosine triphosphate (ATP)/hyaluronidase(Hyals) dually responsive core-shell hyaluronan/chitosan-based drug nanocarrier for breast cancer therapy, using SNX-loaded 3-fluoro-4-carboxyphenylboronic acid-conjugated quaternary ammonium chitosan nanoparticles (SNX@HTCC-FPBA NPs) as the core and crosslinked polyethylene glycol-/methacrylate-modified hyaluronic acid (mHA-PEG) as the shell. The formed SNX@HTCC-FPBA/mHA-PEG NPs were stable against salt ion strength, pH values and human plasma mimicking the bloodstream, but ATP/Hyals dually sensitive with a drug delivery of 85% within 48 h in the mimicking intracellular environment of breast cancer cells. These nanoparticles showed a low hemolysis of less than 3%, a high resistance to bovine serum albumin adsorption of 0.06 mg/mg, and an efficient internalization by two breast cancer cell lines (MCF-7 and MDA-MB-453). The cell culture indicated that they were friendly to human skin fibroblasts, but presented a close IC₅₀ value to SNX for MCF-7 (0.14 μg mL⁻¹) and MDA-MB-453 (0.05 μg mL⁻¹) at 48 h, respectively. Thus, SNX@HTCC-FPBA/mHA-PEG NPs were potential drug nanocarriers for breast tumor therapy.

Polymeric micelles, i.e. aggregation colloids formed in solution by self-assembling of amphiphilic polymers, represent an innovative tool to overcome several issues related to drug administration, from the low water-solubility to the poor drug permeability across biological barriers. With respect to other nanocarriers, polymeric micelles generally display smaller size, easier preparation and sterilization processes, and good solubilization properties, unfortunately associated with a lower stability in biological fluids and a more complicated characterization. Particularly challenging is the study of their interaction with the biological environment, essential to predict the real in vivo behavior after administration. In this review, after a general presentation on micelles features and properties, different characterization techniques are discussed, from the ones used for the determination of micelles basic characteristics (critical micellar concentration, size, surface charge, morphology) to the more complex approaches used to figure out micelles kinetic stability, drug release and behavior in the presence of biological substrates (fluids, cells and tissues). The techniques presented (such as dynamic light scattering, AFM, cryo-TEM, X-ray scattering, FRET, symmetrical flow field-flow fractionation (AF4) and density ultracentrifugation), each one with their own advantages and limitations, can be combined to achieve a deeper comprehension of polymeric micelles in vivo behavior. The set-up and validation of adequate methods for micelles description represent the essential starting point for their development and clinical success.

Nanotechnology is one of the most advanced technologies in the current era. This is attributed to its capabilities to improve the pharmacokinetic profiles of therapeutic and diagnostic agents. Therefore, a large amount of research is focused on developing delivery systems based on this technology. This chapter reviews aspects of widely used nanocarrier systems such as self-assemblies, dendrimers, and polymeric nanoparticles that are used for targeted delivery of therapeutic and diagnostic agents. It highlights critical issues in the design and engineering of nanocarrier systems for various applications. Success stories in the form of examples have been tabulated in this chapter.