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Approval of generic drugs by the US Food and Drug Administration (FDA) requires the product to be pharmaceutically equivalent to the reference listed drug (RLD) and demonstrate bioequivalence (BE) in effectiveness when administered to patients under the conditions in the RLD product labeling. Effectiveness is determined by drug exposure at the target sites. However, since such measurement is usually unavailable, systemic exposure is assumed to equal target site exposure and systemic BE to equal target site BE. This assumption, while it often applies to small molecule drug products that are readily dissolved in biological fluids and systemically absorbed, is unlikely to apply to nanotechnology products (NP) that exist as heterogeneous systems and are subjected to dimension- and material-dependent changes. This commentary provides an overview of the intersecting and spatial-dependent processes and variables governing the delivery and residence of oncologic NP in solid tumors. In order to provide a quantitative perspective of the collective effects of these processes, we used quantitative systems pharmacology (QSP) multi-scale modeling to capture the physicochemical and biological events on several scales (whole-body, organ/suborgan, cell/subcellular, spatial locations, time). QSP is an emerging field that entails using modeling and computation to facilitate drug development; an analogous approach (i.e., model-informed drug development) is advocated by to FDA. The QSP model-based simulations illustrated that small changes in NP attributes (e.g., size variations during manufacturing, interactions with proteins in biological milieu) could lead to disproportionately large differences in target site exposure, rending systemic BE unlikely to equal target site BE.

Nanotechnology offers several attractive design features that have prompted its exploration for cancer diagnosis and treatment. Nanosized drugs have a large loading capacity, the ability to protect the payload from degradation, a large surface on which to conjugate targeting ligands, and controlled or sustained release. Nanosized drugs also leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as the enhanced permeability and retention (EPR) effect. However, while the EPR effect is widely held to improve delivery of nanodrugs to tumors, it in fact offers less than a 2-fold increase in nanodrug delivery compared with critical normal organs, resulting in drug concentrations that are not sufficient for curing most cancers. In this Review, we first overview various barriers for nanosized drug delivery with an emphasis on the capillary wall's resistance, the main obstacle to delivering drugs. Then, we discuss current regulatory issues facing nanomedicine. Finally, we discuss how to make the delivery of nanosized drugs to tumors more effective by building on the EPR effect.