Smart cancer nanomedicine

Abstract

Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve nanomedicine translation and exploitation. (1) Patient stratification has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer nanomedicine therapies.

Figure 1.. Smart Strategies and Materials to Advance and Refine cancer nanomedicine Treatments.

Four directions are proposed that – on their own and especially together – will promote the translation and exploitation of nanomedicinal anticancer drugs.

Figure 2.. Smart strategies for patient stratification in cancer nanomedicine.

Several probes and protocols can be employed for patient stratification, including circulating tumour cell (CTC) analysis, immunohistochemical assessment of the tumour microenvironment, and direct and indirect imaging of nanomedicine tumour accumulation. These approaches vary in simplicity, specificity and applicability for passively versus actively targeted nanomedicines. Liquid biomarkers are the most straightforward and least invasive, but may not be not predictive enough to serve as standalone biomarkers for tailoring nanomedicine treatment. Tissue biomarkers are easily available, but are likely more useful for actively than for passively targeted nanomedicines, and their predictive power needs to be explored. Imaging biomarkers can rely on approved contrast agents and companion nanodiagnostics, which available off the shelf. This contributes to simplicity, but the information obtained may not be specific enough. Nanotheranostics provide highly specific information on the target site accumulation of the formulation in question, but are more challenging from a translational point of view.

Figure 3.. Smart drug selection in cancer nanomedicine.

Rational drug selection is crucial to ensure clinical and commercial success. Multiple strategies can be envisaged to connect the right drug to the right nanocarrier for the right indication. Drug classes: Nanomedicines can be loaded with different types of anticancer drugs, including standard chemotherapeutics, highly potent toxins, biologics and nucleic acids. Prodrugs can be engineered to ensure optimal compatibility with nanocarrier formulations, including e.g. drug coupling via ester linkers to an aliphatic chain for efficient incorporation in lipid-based nanomedicines. Modularity: Nanomedicines can be designed to encapsulate payloads with comparable / compatible properties, such as RNA or small molecule prodrugs. Screening: Nanomedicine libraries can be produced via high-throughput technologies. Various labelling and analytical techniques can be employed to identify nanomedicine candidates with optimal properties for in vivo performance.

Figure 4.. Smart cancer nanomedicine-based combination therapies.

Systemic combinations: (1) Integrating nanomedicines in multimodal chemotherapy regimens results in reduced side effects, better patient compliance and improved quality of life; (2) Co-treatment with approved drugs, such as losartan, helps prime blood vessels and the tumour microenvironment (TME) for improved delivery, thereby enhancing the accumulation, penetration and efficacy of cancer nanomedicines; (3) Nanomedicines enable ratiometric multi-drug delivery, which contributes to synergistic drug effects by improving control over pharmacokinetic and pharmacodynamic interactions. Local combination: (4) Radiotherapy treatment alters the TME to improve the accumulation, penetration, retention and efficacy of cancer nanomedicines. In addition, nanomedicines can potentiate the abscopal effect upon radiotherapy; (5) Ultrasound and microbubbles can induce sonopermeation, thereby increasing vascular perfusion and permeability, and nanomedicine accumulation and efficacy; (6) Hyperthermia can be used to locally trigger payload release from temperature-sensitive liposomes, resulting in increased drug concentrations at the pathological site and less systemic drug exposure, thereby improving the balance between drug efficacy and toxicity.

Figure 5.. Smart immunomodulation involving cancer nanomedicine.

Nanomedicines can be designed to target and modulate components of the adaptive and innate immune systems, thereby improving the outcome of immune checkpoint inhibition therapy. Adaptive immune system-targeted approaches include: (1) Directly targeting antigen-presenting cells by using nanomedicines to deliver (RNA encoding for) tumour antigens and/or drug molecules that modulate co-stimulation and cytokine production. These approaches result in anti-tumour effects mediated via generating and/or activating CD4⁺ and CD8⁺ T cells. (2) Nanomedicines can change the polarization of tumour-associated macrophages (TAM) from a pro-tumour and anti-immunotherapy (M2-like) phenotype into a more anti-tumour and pro-immunotherapy (M1-like) phenotype. (3) Nanomedicines containing chemotherapeutic drugs, such as doxorubicin and oxaliplatin, can boost the induction of immunogenic cell death (ICD), which helps reprogram immunogenically ‘cold’ tumours into ‘hot’ tumours. Innate immune system-targeted approaches include: (4) Reprogramming tumours into an immunogenically ‘hot’ phenotype via the activation of pattern recognition receptors (PRRs), eliciting a type I interferon response and inducing anti-tumour T cell immunity. (5) Nanomedicines can be developed to deliver drugs to myeloid cells and their progenitors in the bone marrow, resulting in specific metabolic and epigenetic changes. The ensuing myeloid cells’ hyperresponsiveness towards secondary stimuli has become known as “trained immunity” and may help improve the efficacy of (checkpoint inhibition-based) cancer immunotherapy.