Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval

Abstract

Over the last three decades, polymeric micelles have emerged as a highly promising drug delivery platform for therapeutic compounds. Particularly, poorly soluble small molecules with high potency and significant toxicity were encapsulated in polymeric micelles. Polymeric micelles have shown improved pharmacokinetic profiles in preclinical animal models and enhanced efficacy with a superior safety profile for therapeutic drugs. Several polymeric micelle formulations have reached the clinical stage and are either in clinical trials or are approved for human use. This furthers interest in this field and underscores the need for additional learning of how to best design and apply these micellar carriers to improve the clinical outcomes of many drugs. In this review, we provide detailed information on polymeric micelles for the solubilization of poorly soluble small molecules in topics such as the design of block copolymers, experimental and theoretical analysis of drug encapsulation in polymeric micelles, pharmacokinetics of drugs in polymeric micelles, regulatory approval pathways of nanomedicines, and current outcomes from micelle formulations in clinical trials. We aim to describe the latest information on advanced analytical approaches for elucidating molecular interactions within the core of polymeric micelles for effective solubilization as well as for analyzing nanomedicine's pharmacokinetic profiles. Taking into account the considerations described within, academic and industrial researchers can continue to elucidate novel interactions in polymeric micelles and capitalize on their potential as drug delivery vehicles to help improve therapeutic outcomes in systemic delivery.

Keywords: Active pharmaceutical ingredient; Block copolymer; Clinical trials; Drug; Drug delivery; Polymeric micelle; Solubilization.

Figure 1.

Schematic illustration of polymeric micelles for delivery of poorly soluble drugs

Figure 2.

Comparison of various paclitaxel (PTX) formulations that are either clinically approved (Abraxane and Taxol by USFDA, Genexol-PM by South Korea’s Ministry of Food and Drug Safety) or undergone clinical trials (NK105) with the POx/PTX polymeric micelle formulation. Taxol contains only about 1% wt. of active ingredient (m(PTX)_max/m(total)), while Genexol-PM and NK105 have much higher drug loadings. The maximal paclitaxel concentration in solution (PTX_max) achieved with all four formulations is below 10 g/L, while POx/PTX can reach almost 50 g/L. Compared to Abraxane and POx-PTX, NK105 and Genexol-PM formulations are significantly diluted down for injection, so that final PTX concentrations ([PTX]_inj) are well below 1 g/L [6, 7]. Of all compared PTX formulations, the novel POx/PTX polymeric micelle formulation exhibits the highest maximum tolerated dose (MTD) in mice. Reprinted with permission from [22] Copyright 2016, Elsevier.

Figure 3.

Study design of cheminformatics-driven discovery of polymeric micelle formulations for poorly soluble drugs. From [116]. Reprinted with permission from AAAS.

Figure 4.

(A) Partitioning coefficients of CH₃−(CH₂)_N−Flu probes vs the number of methylene groups in the alkyl radical obtained for P103, P105, and F108. (B) Schematic presentation of Pluronic micelle using spherical lattice model described in [–225]. Hydrophobic PO units (black filled circles) localize in the central part of the micelle, while hydrophilic EO units (black empty circles) and water molecules (empty cells) fill external layers. Parts a−c show incorporation of a solute (probe) having alkyl radicals of varying length (gray filled circles) and a polar fluorescent group (gray empty circle). Note unfavorable contacts between hydrophobic groups of the solute and water molecules or EO units in the case of the probes with shorter radicals. Reprinted with permission from [29] Copyright 2009, American Chemical Society.

Figure 5.

Schematic model of the structural changes of the polymeric micelles upon loading with curcumin based on the solid-state NMR data and complementary insights. For each loading stage, the additionally occurring interaction site is depicted. Reproduced with permission from [65].

Figure 6.. A three-compartmental model describing the PM drug delivery to a tumor.

The drug is administered as bolus in the form of PM (1) and is subsequently distributed between the plasma (2) and tumor (3) compartments. The PK constants correspond to: k12 - rate of drug transfer from PM to plasma; k21 – rate of drug re-capture from plasma to PM; k13 - rate of transfer (permeability) of the micellar drug to tumor; k23 - rate of transfer of the plasma bound drug to tumor; k31 and k32 – rates of drug reabsorption from tumor to PM and plasma, respectively; k10 and k20 - micellar and plasma 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 with permission from [188].

Figure 7.

The drug amount-time profiles for the tumor obtained using a three-compartmental model. Simulations for basic scenarios A (solid lines) and B (dashed lines) are shown. The three-compartmental model is presented in Figure 6 and the values of the PK parameters used in simulation were varied. In the A scenario, the penetration of micellar bound drug into the tumor is much less than that of plasma bound drug. In scenario B, the micellar bound drug penetration is comparable to that of plasma bound drug. As you move through A0 and B0 up to A5 and B5, this shows the effect of increased drug retention in the micelle. All units are arbitrary. Reprinted with permission from [188].

Figure 8.

Multiple chemotherapeutic agents in high capacity poly(2-oxazoline) micelles. (Drug designations: BTZ – bortezomib, DTX – docetaxel, ETO – etoposide, PTX – paclitaxel) Reprinted with permission from [117] Copyright 2012, American Chemical Society.