Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

Abstract

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogelbased nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications. A long-term goal in contemporary cancer nanomedicine has been to design and generate drug delivery systems that improve the narrow therapeutic window associated with conventional chemotherapeutics (1, 2). Conceptually, several nanotechnologybased entity candidates, including protocells (3), biosynthetic nanoparticles (NPs), viruses, and liposome-based nanoparticles, could be targeted for active delivery through a defined cell surface ligand receptor system and/or physically triggered for finely tuned cargo release (2, 4, 5).Numerous efforts have been made to functionalize NPs by combining them with antibodies, aptamers, peptides, vitamins, or carbohydrates (6-8), but the majority of studies involve untargeted nanoplatforms (4, 9). In practice, targeting NPs is far from trivial, and ongoing challenges include synthesis and purification, selection of an appropriate ligand receptor, and specific composition for NP conjugation. Even the conjugation reaction itself may alter the binding of the tumor-targeting moiety to its receptor through conformational changes, steric freedom restriction, or orientation distortion (10, 11). Unfortunately, the SignificanceThe main goal in the emerging field of cancer nanomedicine is to generate, standardize, and produce multifunctional carriers designed to improve the response of drugs against tumors. Here we report the design, development, and preclinical validation of a ligand-directed bioinorganic platform that integrates tumor targeting, receptor-mediated cell internalization, photon-to-heat conversion, and drug delivery. This enabling hydrogel-based technology can accommodate a broad variety of ligands, nanoparticles, and payloads. We show experimental proof-of-concept in mouse models of breast and prostate cancer with molecular imaging and marked reduct...

Size‐Optimized Ultrasmall Porous Silica Nanoparticles Depict Vasculature‐Based Differential Targeting in Triple Negative Breast Cancer

“…Unlike our previous modeling approaches to study tissue disposition kinetics and tumor delivery efficacy of NPs, here we developed a multicompartment, semimechanistic model, which is a reduced physiologically based PK (PBPK) model, comprising a systemic blood pool, RES (i.e., liver and spleen), muscle, and a facultative tumor compartment (applicable for tumor‐bearing groups only), which represent the dominant distribution sites of the UPSNs in vivo, connected in an anatomical fashion via plasma (red arrows) and lymph (blue arrows) flow (Figure C and Figure S7, Supporting Information). In traditional PK modeling, organs are modeled as well‐stirred, black‐box like compartments with homogenous, time‐dependent exposure to administered drugs .…”

Mathematical modeling in cancer nanomedicine: a review

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