| Abstract: | ![]()
Nanomedicines (NMs) offer new solutions for cancer diagnosis and therapy. However, extension of progression-free interval and overall survival time achieved by Food and Drug Administration-approved NMs remain modest. To develop next generation NMs to achieve superior anticancer activities, it is crucial to investigate and understand the correlation between the physicochemical properties of NMs (particle size in particular) and their interactions with biological systems to establish criteria for NM optimization. Here, we systematically evaluated the size-dependent biological profiles of three monodisperse drug–silica nanoconjugates (NCs; 20, 50, and 200 nm) through both experiments and mathematical modeling and aimed to identify the optimal size for the most effective anticancer drug delivery. Among the three NCs investigated, the 50-nm NC shows the highest tumor tissue retention integrated over time, which is the collective outcome of deep tumor tissue penetration and efficient cancer cell internalization as well as slow tumor clearance, and thus, the highest efficacy against both primary and metastatic tumors in vivo.Over the last two to three decades, consensus has been reached that the size of anticancer nanomedicines (NMs) plays a pivotal role in determining their biodistribution, tumor penetration, cellular internalization, and clearance from blood plasma and tissues as well as excretion from body, and thus, it has significant impact on overall therapeutic efficacy against cancers (1–7). Although most clinically approved anticancer NMs have size ranging from 100 to 200 nm (8, 9), recent studies showed that anticancer NMs with smaller sizes exhibited enhanced performance in vivo, such as greater tissue penetration and enhanced tumor inhibition, particularly those with size around or smaller than 50 nm (5–7, 10–12). As such, there has been a major push recently in the field of anticancer NM to miniaturize nanoparticle (NP) size using novel chemistry and engineering design (13–17). One unanswered question, however, is whether additional miniaturization of NM size would be necessary and result in additional improved anticancer efficacy. Widely evaluated small molecular therapeutics (<1,500 Da and <2 nm) can traverse most tumor tissues freely (18). However, they diffuse away from tumor tissues rapidly and get cleared primarily into tumor blood capillaries, leading to minimal tumor accumulation (18). Macromolecules of relatively low molecular masses (<40,000 Da and <10 nm) were also shown to have low overall tumor retention because of both rapid permeation into and clearance from tumor tissues, behaving to some extent like small molecule drugs (18, 19). In conjunction with the renal clearance threshold (<10–15 nm) (20, 21) and interstitial/lymphatic fenestration (<20 nm) (22) for NPs, it becomes essential to carefully and comprehensively evaluate the in vivo behavior and anticancer efficacy of NMs in the size range of 20–50 nm to determine the optimal size of NM for cancer therapy.In this study, we used monodisperse drug–silica nanoconjugates (NCs) that have identical physiochemical properties, except for size, to investigate the size-dependent biodistribution and tumor tissue penetration and clearance as well as the overall efficacy. We focused on the NCs of 20 and 50 nm in this particularly interesting size range as well as the NC of 200 nm, the upper size limit of systemic NM to extravasate leaky tumor vasculature, which has a cutoff pore size larger than 200 nm for most tumors (23). Among these three representative sizes, the 50-nm NC showed the optimal balance of deep tissue penetration and high retention in tumors, which is in contrast with its larger counterpart (the 200-nm NC) of limited tumor tissue penetration and smaller counterpart (the 20-nm NC) of fast clearance from tumors, leading to overall low tumor retention for both. Therefore, 50 nm could be or could be close to the optimal size of NCs in the studied size range of 20–200 nm, ensuring not only the efficient distribution in, but also the protracted availability of drug-containing NC to the tumor tissues, resulting in superior anticancer efficacy against both primary and metastatic tumors. |
