Injected nanocrystals for targeted drug delivery

Abstract

Nanocrystals are pure drug crystals with sizes in the nanometer range. Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs. Nanocrystals in the blood stream can be recognized and sequestered as exogenous materials by mononuclear phagocytic system (MPS) cells, leading to passive accumulation in MPS-rich organs, such as liver, spleen and lung. Particle size, morphology and surface modification affect the biodistribution of nanocrystals. Ligand conjugation and stimuli-responsive polymers can also be used to target nanocrystals to specific pathogenic sites. In this review, the progress on injected nanocrystals for targeted drug delivery is discussed following a brief introduction to nanocrystal preparation methods, i.e., top-down and bottom-up technologies.

Keywords: Biodistribution; Encapsulation; Ligand; Nanocrystals; Stimuli response; Targeted drug delivery.

Graphical abstract

Figure 1

Illustration of the media milling process. A crude slurry consisting of drug, water and stabilizer is fed into the milling chamber, which is agitated by a motor. The particle size of drug powders is reduced by shearing forces and impaction between milling media and drug. Recirculation can increase the milling efficiency, while the coolant can control the temperature of the materials. The milling time required to generate nanocrystals depends on the properties of the drugs, the milling media and the extent of particle size reduction, varying from hours to days.

Figure 2

Illustration of the high pressure homogenization process. Pretreated drug suspensions are forced through a tiny gap or specially designed homogenization chamber (Z- or Y- type) under high pressure, typically 1500–2000 bar. During this process, cavitation generated by high streaming velocity, together with high shear forces and collisions among particles, comminute big drug crystals to nanocrystals. A high number of passes, such as 50–100 passes, is still required even under 1700 bar to obtain the desirable particle size and size distribution.

Figure 3

Schematic illustration of bottom-up techniques in which crystallization is triggered by solvent/anti-solvent mixing. Sonication can be combined with a common mixing instrument such as magnetic stirring to promote nucleation (A). With highly efficient mixing equipment, including confined impinging jet reactor (B), multiple inlet vortex mixer (C) and static mixer (D), intense micro-mixing may be achieved even before the onset of nucleation, favoring small and homogeneous nanocrystals.