Guidelines for Rational Cancer Therapeutics

Abstract

Traditionally, cancer therapy has relied on surgery, radiation therapy, and chemotherapy. In recent years, these interventions have become increasingly replaced or complemented by more targeted approaches that are informed by a deeper understanding of the underlying biology. Still, the implementation of fully rational patient-specific drug design appears to be years away. Here, we present a vision of rational drug design for cancer that is defined by two major components: modularity and image guidance. We suggest that modularity can be achieved by combining a nanocarrier and an oligonucleotide component into the therapeutic. Image guidance can be incorporated into the nanocarrier component by labeling with a specific imaging reporter, such as a radionuclide or contrast agent for magnetic resonance imaging. While limited by the need for additional technological advancement in the areas of cancer biology, nanotechnology, and imaging, this vision for the future of cancer therapy can be used as a guide to future research endeavors.

Keywords: cancer; imaging; nanomedicine; rational; therapy.

Figure 1

Structures and frontier orbitals (red/blue) for (A) locked nucleic acid (LNA) with the sequence 5′-AAG-3′ (5′ end at bottom of structure) and (B) LNA with sequence 5′-AAG-3′, chemically modified by phosphorothioate internucleoside linkages (PS). The electrostatic potential (negative) is shown in gray and represented by an Iso-potential value of −83 kJ/mol. Reproduced from Ref. (10) with kind permission by Mary Ann Liebert, Inc.

Figure 2

DNA barcoded nanoparticles for high-throughput in vivo nanoparticle delivery. (A) Using high-throughput fluidic mixing, nanoparticles are formulated to carry a DNA barcode. (B) Many nanoparticles can be formulated in a single day; each nanoparticle chemical structure carries a distinct barcode. Particles are then combined and administered simultaneously to mice. Tissues are then isolated, and delivery is quantified by sequencing the barcodes. In this example, nanoparticle 1 delivers to the lungs, nanoparticle 2 delivers to the liver, and nanoparticle N delivers to the heart. (C) This DNA barcode system enables multiplexed nanoparticle-targeting studies in vivo, improving upon the current practice, which relies on in vitro nanoparticle screening to identify lead candidates. Reproduced from Ref. (23) with kind permission by the National Academy of Sciences.

Figure 3

A modular strategy for diversifying the chemical functionality and size of ester-based dendrimers allowed discovery of potent and nontoxic dendrimers for in vivo small-RNA delivery to tumor cells. (A) Orthogonal reactions accelerated the synthesis of >1,500 modular degradable dendrimers by combination of 42 cores (C) and 36 peripheries (P) through degradable linkages (L) and generations. The library was established via sequential reactions. First, amines (C) with a series of N–H bonds reacted quantitatively and selectively with the less steric acrylate groups of AEMA (L). The products (C–L) then quantitatively reacted with various thiols (P) under optimized DMPP-catalyzed conditions. (B) Dendrimers were independently modulated with chemically diverse amines and thiols. Selected amines were divided into two categories: ionizable amines (1A–6A) to tune RNA binding from C that generated one to six branched dendrimers, and alkyl amines (1H–2H) to tune NP C stabilization. Alkyl thiols (SC1–SC19) and alcohol/carboxylic acid terminated thiols (SO1–SO9) were selected to tune NP P stabilization. Aminothiols (SN1–SN11) were selected to tune P RNA binding. G2–G4 higher generation dendrimers with multiple branches were also synthesized using generation expansion reactions. Reproduced from Ref. (24) with kind permission by the National Academy of Sciences.

Figure 4

A multimodal approach for the non-invasive assessment of drug bioavailability and therapeutic effect in a model of prostate cancer. (A) Representative SPECT images of a SCID mouse bearing PC3-PIP and PC3-Flu tumors. (B) In vivo total choline density maps from 2D CSI datasets acquired from a representative PC3-PIPtumor (~400 mm³) before and 48 h after i.v. injection of the PSMA-targeted nanoplex 1 (150 mg/kg). (C) In vivo ¹⁹FMR spectra acquired from a PC3-PIP tumor (~400 mm³) at 24 and 48 h after i.v. injection of the PSMA-targeted nanoplex (150 mg/kg) carrying bCD and siRNA-Chk. Reproduced from Ref. (25) with kind permission by the American Chemical Society.

Figure 5

T2-weighted magnetic resonance imaging of MN-anti-miR10b accumulation in orthotopic MDA-MB-231-luc-D3H2LN tumors. (A) Representative color-coded T2 maps before (left) and 24 h after (right) MN-anti-miR10b injection demonstrating a shortening of the T2 relaxation times of the tumors (outlined) consistent with nanodrug accumulation. (B) Quantitative analysis of ΔR2 relaxation rates (1/T2 pre − 1/T2 post, ms) of the tumors, suggesting a tendency toward build-up of the MN-anti-miR10b (p ≤ 0.01, n = 12). Data are represented as mean ± SD. Reproduced from Ref. (29) with kind permission by Nature Publishing Group.

Figure 6

Modular labeling for in vivo positron emission tomography (PET) imaging of tumor-homing nanoparticles. (A) Radioactivity distribution in selected tissues of ⁸⁹Zr-SCL and ⁸⁹Zr-CLL. (B) PET/computerized tomography (CT) imaging of ⁸⁹Zr-SCL: CT only (left), PET/CT fusion (middle), and 3-dimensional rendering of PET/CT fusion (right) at 24 h after injection. Reproduced from Ref. (32) with kind permission by the Society of Nuclear Medicine and Molecular Imaging.