Nature employs a variety of tactics to precisely time and execute the processes and mechanics of life, relying on sequential sense and response cascades to transduce signaling events over multiple length and time scales. Many of these tactics, such as the activation of a zymogen, involve the direct manipulation of a material by a stimulus. Similarly, effective therapeutics and diagnostics require the selective and efficient homing of material to specific tissues and biomolecular targets with appropriate temporal resolution. These systems must also avoid undesirable or toxic side effects and evade unwanted removal by endogenous clearing mechanisms. Nanoscale delivery vehicles have been developed to package materials with the hope of delivering them to select locations with rates of accumulation and clearance governed by an interplay between the carrier and its cargo. Many modern approaches to drug delivery have taken inspiration from natural activatable materials like zymogens, membrane proteins, and metabolites, whereby stimuli initiate transformations that are required for cargo release, prodrug activation, or selective transport. This Perspective describes key advances in the field of stimuli-responsive nanomaterials while highlighting some of the many challenges faced and opportunities for development. Major hurdles include the increasing need for powerful new tools and strategies for characterizing the dynamics, morphology, and behavior of advanced delivery systems in situ and the perennial problem of identifying truly specific and useful physical or molecular biomarkers that allow a material to autonomously distinguish diseased from normal tissue.
In this Communication, we describe an enzyme-responsive, paclitaxel-loaded nanoparticle and assess its safety and efficacy in vivo in a human fibrosarcoma murine xenograft. The material was generated via graft-through block copolymerization of norbornene monomers with hydrophilic targeting peptides together with hydrophobic paclitaxel prodrugs. This work represents a proof-of-concept study demonstrating the utility of enzyme-responsive nanoscale drug carriers capable of targeted accumulation and retention in tumor tissue in response to overexpressed endogenous enzymes. Critically, we observed low systemic toxicity in healthy mice following intravenous administration, with the maximum tolerated dose (MTD) exceeding 240 mg/kg with respect to paclitaxel. Furthermore, we observed efficacy against tumorigenesis paralleling that of paclitaxel at equivalent intravenous dosing, and near complete tumor growth suppression when administered intratumorally. This work represents a significant departure from traditional targeted drug delivery systems and presents a new avenue of exploration for nanomedicine.
Highly heterogenous cancers, such as triple-negative breast cancer (TNBC), remain challenging immunotherapeutic targets. Herein, we describe the synthesis and evaluation of immunotherapeutic liposomal spherical nucleic acids (SNAs) for TNBC therapy. The SNAs comprise immunostimulatory oligonucleotides (CpG-1826) as adjuvants and encapsulate lysates derived from TNBC cell lines as antigens. The resulting nanostructures (Lys-SNAs) enhance the codelivery of adjuvant and antigen to immune cells when compared to simple mixtures of lysates with linear oligonucleotides both in vitro and in vivo, and reduce tumor growth relative to simple mixtures of lysate and CpG-1826 (Lys-Mix) in both Py230 and Py8119 orthotopic syngeneic mouse models of TNBC. Furthermore, oxidizing TNBC cells prior to lysis and incorporation into SNAs (OxLys-SNAs) significantly increases the activation of dendritic cells relative to their nonoxidized counterparts. When administered peritumorally in vivo in the EMT6 mouse mammary carcinoma model, OxLys-SNAs significantly increase the population of cytotoxic CD8+ T cells and simultaneously decrease the population of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment, when compared with Lys-SNAs and simple mixtures of oxidized lysates with CpG-1826. Importantly, animals administered OxLys-SNAs exhibit significant antitumor activity and prolonged survival relative to all other treatment groups, and resist tumor rechallenge. Together, these results show that the way lysates are processed and packaged has a profound impact on their immunogenicity and therapeutic efficacy. Moreover, this work points toward the potential of oxidized tumor cell lysate-loaded SNAs as a potent class of immunotherapeutics for cancers lacking common therapeutic targets.
In this Account, we describe the organization of functional peptides as densely arrayed side chains on polymer scaffolds which we introduce as a new class of material called poly(peptide). We describe two general classes of poly(peptide): (1) Peptide−Polymer Amphiphiles (PPAs), which consist of block copolymers with a dense grouping of peptides arrayed as the side chains of the hydrophilic block and connected to a hydrophobic block that drives micelle assembly, and (2) Protein-like Polymers (PLPs), wherein peptide-brush polymers are composed from monomers, each containing a peptide side chain. Peptides organized in this manner imbue polymers or polymeric nanoparticles with a range of functional qualities inherent to their specific sequence. Therefore, polymers or nanoparticles otherwise lacking bioactivity or responsiveness to stimuli, once linked to a peptide of choice, can now bind proteins, enter cells and tissues, have controlled and switchable biodistribution patterns, and be enzyme substrates (e.g., for kinases, phosphatases, proteases). Indeed, where peptide substrates are incorporated, kinetically or thermodynamically driven morphological transitions can be enzymatically induced in the polymeric material. Synergistically, the polymer enforces changes in peptide activity and function by virtue of packing and constraining the peptide. The scaffold can protect peptides from proteolysis, change the pharmacokinetic profile of an intravenously injected peptide, increase the cellular uptake of an otherwise cell impermeable therapeutic peptide, or change peptide substrate activity entirely. Moreover, in addition to the sequencecontrolled peptides (generated by solid phase synthesis), the polymer can carry its own sequence-dependent information, especially through living polymerization strategies allowing well-defined blocks and terminal labels (e.g., dyes, contrast agents, charged moieties). Hence, the two elements, peptide and polymer, cooperate to yield materials with unique function and properties quite apart from each alone. Herein, we describe the development of synthetic strategies for accessing these classes of biomolecule polymer conjugates. We discuss the utility of poly(peptide)-based materials in a range of biomedical applications, including imaging of diseased tissues (myocardial infarction and cancer), delivering small molecule drugs to tumors with high specificity, imparting cell permeability to otherwise impermeable peptides, protecting bioactive peptides from proteolysis in harsh conditions (e.g., stomach acid and whole blood), and transporting proteins into traditionally difficult-to-transfect cell types, including stem cells. Poly(peptide) materials offer new properties to both the constituent peptides and to the polymers, which can be tuned by the design of the oligopeptide sequence, degree of polymerization, peptide arrangement on the polymer backbone, and polymer backbone chemistry. These properties establish this approach as valuable for the development of peptides as medicines and materials...
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