br Nanomedicines are a diverse collection of nanoscale
Nanomedicines are a diverse collection of nanoscale materials measuring approximately 5-150 nm in mean diameter. These include therapeutic, diagnostic, and theranostic compounds (which are simultaneously therapeutic and diagnostic). Most clinically-approved nanomedicines for oncology are macromolecular drug carriers designed to improve tumoral delivery of drugs. These include liposomes, polymeric micelles, protein-drug conjugates, polymer-drug conjugates, dendrimers, and inorganic nanoparticles (NPs)9. The conjugation to or encapsulation within a NP drug carrier imparts a number of pharmacokinetic and pharmacodynamic advantages including improved solubility and more favorable biodistribution. The most consistent benefit of chemotherapeutic NP drug-delivery systems is an improved therapeutic index9-11. Owing to their increased size, NPs are largely unable to penetrate normal tissues. However, NPs can more readily exit systemic circulation and enter the extracellular space in tumors because of their relatively disorganized and leaky vasculature. As a result, NP drug carriers are preferentially excluded from normal tissues and retained in tumors. This phenomenon is referred to as the enhanced permeability and retention (EPR) effect12,13. The benefits of NP delivery systems go far beyond improved biodistribution. These systems are highly tunable with respect to most physical properties including shape, size, charge, hydrophobicity, and chemical composition. This tunability enables precise control over characteristics including tissue penetrability and in vivo drug release rates in ways not possible with other drug delivery methods14,15. It is also possible to design stimulus-responsive NPs that are destabilized or release their cargo when stimulated by specific physiochemical cues using various chemical linkers or elements16-18. Finally, the particle surface can be decorated with various moieties including saccharides, polymers, proteins, or Ambuic Acid to avoid immune detection and improve targeting and receptor-mediated uptake within specific cell populations.
2. Overcoming Barriers to NP Delivery
Despite the above-highlighted advantages of NP delivery systems, a number of challenges related to in vivo delivery have limited them from reaching their full potential. Most clinically-utilized NPs for oncology have been untargeted NP formulations of existing chemotherapeutics that rely on the EPR and passive tumor-targeting to enhance tumoral drug concentrations. However, the clinical relevance of the EPR and passive tumor targeting in many spontaneous human tumors has been called into question19,20. It is now recognized that many of the vascular irregularities underlying the EPR in xenograft tumor models are more extreme than those observed in spontaneous tumors. Tumor xenografts also tend to lack well-developed tumor stroma which can also act as a barrier to diffusion21. As a result, spontaneous human tumors may be less susceptible to passive tumor targeting by the EPR effect than previously predicted in preclinical models. This has been experimentally confirmed in clinical studies using radiolabeled or imageable ferromagnetic NPs in spontaneous solid tumors22-24. Uptake and retention of NPs in spontaneous tumors is generally more heterogeneous than in xenograft models. Many particles that reach the extracellular tumor space are either retained there without entering tumor cells or are cleared by tumoral macrophages prior to payload delivery. For many small molecule drugs, particularly hydrophobic ones that can readily diffuse across cell membranes, extracellular delivery may be sufficient to exert their intended effects. However, macromolecular cargos such as
peptides and nucleic acids require efficient uptake and intact cytoplasmic or nuclear delivery to be effective. Clearance by phagocytic cell populations can substantially limit their efficacy.
Some of these issues may be less problematic for immune-stimulating nanomedicines than traditional chemotherapy-delivering compounds. Heterogeneous uptake and retention may be sufficient for immune-stimulating NPs. Compared to cytotoxic chemotherapies, many potent immune adjuvants are effective at relatively low concentrations. As highlighted in Figure 1, heterogeneous uptake of chemotherapy-loaded NPs is sub-optimal and requires high tumoral dosing because only the tumor cells in proximity to the drug-loaded NPs will be affected. In contrast, the delivery of proinflammatory cytokines to a small number of antigen presenting cells (APCs) can stimulate a chain reaction leading to the recruitment and activation of multiple populations of inflammatory cells to initiate immune-mediated tumor clearance. Additionally, many of the targets of immunotherapy are not tumor cells but rather populations of immune cells found in the TME. Novel imaging studies have demonstrated that resident and recruited populations of tumor immune cells are primarily localized to the tumor periphery and perivascular regions of the TME which are easily accessible by most NPs25. These include phagocytic cell populations such as APCs and tumor associated macrophages (TAMs). Whereas phagocytic clearance is problematic for tumor-targeting NPs, it can actually be advantageous for novel NPs targeting non-tumor cell populations in the TME. Most novel cancer nanoimmunotherapies are “next generation” NPs engineered to address or take advantage of limitations encountered with previous generations of NPs. Several major concepts are reviewed here to highlight advanced delivery techniques utilized by these nanomedicines.