Targeted Polymersome Delivery of a Stapled Peptide for Drugging the Tumor Protein p53:BCL-2-Family Axis in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) remains a formidable diagnosis in need of new treatment paradigms. In this work, we elucidated an opportunity for therapeutic synergy in DLBCL by reactivating tumor protein p53 with a stapled peptide, ATSP-7041, thereby priming cells for apoptosis and enhancing their sensitivity to BCL-2 family modulation with a BH3-mimetic, ABT-263 (navitoclax). While this combination was highly effective at activating apoptosis in DLBCL in vitro, it was highly toxic in vivo, resulting in a prohibitively narrow therapeutic window. We, therefore, developed a targeted nanomedicine delivery platform to maintain the therapeutic potency of this combination while minimizing its toxicity via packaging and targeted delivery of a stapled peptide. We developed a CD19-targeted polymersome using block copolymers of poly(ethylene glycol) disulfide linked to poly(propylene sulfide) (PEG-SS-PPS) for ATSP-7041 delivery into DLBCL cells. Intracellular delivery was optimized in vitro and validated in vivo by using an aggressive human DLBCL xenograft model. Targeted delivery of ATSP-7041 unlocked the ability to systemically cotreat with ABT-263, resulting in delayed tumor growth, prolonged survival, and no overt toxicity. This work demonstrates a proof-of-concept for antigen-specific targeting of polymersome nanomedicines, targeted delivery of a stapled peptide in vivo, and synergistic dual intrinsic apoptotic therapy against DLBCL via direct p53 reactivation and BCL-2 family modulation.

Advances in Polymer Design for Enhancing Oral Drug Solubility and Delivery.

Synthetic polymers have enabled amorphous solid dispersions (ASDs) to emerge as an oral delivery strategy for overcoming poor drug solubility in aqueous environments. Modern ASD products noninvasively treat a range of chronic diseases (for example, hepatitis C, cystic fibrosis, and HIV). In such formulations, polymeric carriers generate and maintain drug supersaturation upon dissolution, increasing the apparent drug solubility to enhance gastrointestinal barrier absorption and oral bioavailability. In this Review, we outline several approaches in designing polymeric excipients to drive interactions with active pharmaceutical ingredients (APIs) in spray-dried ASDs, highlighting polymer-drug formulation guidelines from industrial and academic perspectives. Special attention is given to new commercial and specialized polymer design strategies that can solubilize highly hydrophobic APIs and suppress the propensity for rapid drug recrystallization. These molecularly customized excipients and hierarchical excipient assemblies are promising toward informing early-stage drug-discovery development and reformulating existing API candidates into potentially lifesaving oral medicines for our growing global population.

Molecular engineering solutions for therapeutic peptide delivery.

Proteins and their interactions in and out of cells must be well-orchestrated for the healthy functioning and regulation of the body. Even the slightest disharmony can cause diseases. Therapeutic peptides are short amino acid sequences (generally considered <50 amino acids) that can naturally mimic the binding interfaces between proteins and thus, influence protein-protein interactions. Because of their fidelity of binding, peptides are a promising next generation of personalized medicines to reinstate biological harmony. Peptides as a group are highly selective, relatively safe, and biocompatible. However, they are also vulnerable to many in vivo pharmacologic barriers limiting their clinical translation. Current advances in molecular, chemical, and nanoparticle engineering are helping to overcome these previously insurmountable obstacles and improve the future of peptides as active and highly selective therapeutics. In this review, we focus on self-assembled vehicles as nanoparticles to carry and protect therapeutic peptides through this journey, and deliver them to the desired tissue.