" Yin-Yang philosophy" for the design of anticancer drug delivery nanoparticles

Abstract

Understanding the in vivo transport process provides guidelines for designing ideal nanoparticles (NPs) with higher efficacy and fewer off-target effects. Many factors, such as particle size, morphology, surface potential, structural stability, and etc., may influence the delivering process of NPs due to the existence of various physiological barriers within the body. Herein, we summarise the distinct influences of NP physicochemical properties on the four consecutive in vivo transport steps: (1) navigating with bloodstream within blood vessels, (2) transport across vasculature walls into tumour tissues, (3) intratumoural transport through the interstitial space, and (4) cellular uptake & intracellular delivery by cancerous cells. We found that the philosophy behind the current consensus for NP design has certain similarities to the "Yin-Yang" theory in traditional Chinese culture. Almost all physicochemical properties, regardless of big or small sizes, long or short length, positive or negative zeta potentials, are double-edged swords. The balance of potential benefits and side effects, drug selectivity and accessibility should be fully considered when optimising particle design, similar to the "Yin-Yang harmony". This paper presents a comprehensive review of the advancements in NPs research, focusing on their distinct features in tumour targeting, drug delivery, and cell uptake. Additionally, it deliberates on future developmental trends and potential obstacles, thereby aiming to uncover the ways these characteristics influence the NPs' biological activity and provide theoretical guidance for the targeted delivery of NPs.

Keywords: in vivo drug delivery; nanoparticle design; on-demand drug release; targeting strategy; “Yin-Yang harmony”.

Figure 1.. Schematic representation of the size dependence of NP delivery in vivo. Both large and small particle sizes owned respective advantages and disadvantages during the transport process. Smaller nanoparticles (< 10 nm in diameter) can permeate through most tissues with high efficiency, but NPs smaller than 5–6 nm are quickly cleared by the kidneys. NPs larger than 100 nm are easy to be captured by the liver, spleen, etc. When the diameters exceed 200 nm, the NPs are more likely to experience quick clearance by the RES. It is reported that the optimal diameter of therapeutic NPs should be in the range of 10–100 nm. Created with Microsoft PowerPoint (version Microsoft 365). NP: nanoparticle; RES: reticuloendothelial system.

Figure 2.. Schematic representation of the surface charge dependence of NP delivery in vivo. Cationic NPs have a higher degree of cellular internalisation than anionic ones in certain cancers, but they are more attractive to plasma proteins, resulting in a shorter circulation time. Neutral particles diffuse more rapidly within the tumour interstitial space than either cationic or anionic counterparts. It is suggested that neutral NPs (±10 mV), especially those with a slight positive charge (between 0 to 10 mV), may be preferred for anticancer drug delivery. Created with Microsoft PowerPoint (version Microsoft 365). NP: nanoparticle.

Figure 3.. Schematic representation illustrating various modes of entry for nanorods with diverse aspect ratios. Short NRs penetrate tip-first, resembling a “rocket” mode of entry (upper panel), whereas NRs with a high AR enter side-first, with their long axis parallel to the membrane, akin to a “submarine mode” (lower panel). Created with Microsoft PowerPoint (version Microsoft 365). AR: aspect ratio; NR: nanorod.

Figure 4.. Schematic representation of the current classification of tumour targeting strategies. The abscissa represents the dimension of active and passive targeting, and the ordinate represents another dimension of dynamic and static targeting. Based on this description, different targeting strategies can be classified and localised in different quadrants. Created with Microsoft PowerPoint (version Microsoft 365). EPR effect: enhanced permeability and retention effect.

Figure 5.. The philosophy behind the current consensus for NP design has certain similarities with “Yin-Yang balance” theory. Both “Yin” and “Yang” of each physicochemical properties have pros and cons for drug delivery, the balance of which should be considered before the final design. An ideal drug delivery system should be stable during circulation (i) while unstable when reach target tumour issues and cells (ii). Macrophages act as a major limitation for nanotherapeutic delivery, while TAM might be utilized for drug delivery, as “Yin is within, but not against Yang”. Created with Microsoft PowerPoint (version Microsoft 365). NP: nanoparticle; TAM: tumour-associated macrophage.