Poly (ortho esters) (POEs) as cutting-edge biodegradable polymers for targeted cancer treatment and overcoming multidrug resistance

Abstract Poly (ortho esters) (POEs), biodegradable polymers featuring acid-labile ortho ester bonds formed through diol-diketene acetal reactions, are transforming cancer treatment with pH-sensitive surface erosion. This analysis explores the development of Poly (ortho ester) I, II, III, and IV (POE I–IV), suggesting that their adjustable degradation and controlled drug release may address multidrug resistance (MDR) and transform targeted cancer treatment. We seek to highlight the structural adaptability of POEs, their therapeutic functions, and their potential as advanced drug delivery systems. POE I, developed in the 1970s, faced challenges with autocatalytic degradation. POE II brought in neutral byproducts for enhanced stability, POE III facilitated injectable semi-solid formulations, and POE IV, the ultimate advancement, incorporates latent acid segments for self-catalyzed hydrolysis in acidic tumour micro environments (pH 6.5–6.8), removing the need for external excipients. POE nanoparticles (50–300 nm) flexibly modify their size to improve tumour infiltration through the enhanced permeability and retention effect. Surface alterations, such as PEGylation or ligand attachment (e.g., folic acid), enable accurate targeting while minimizing systemic toxicity. POEs are proficient in jointly delivering chemotherapeutics and immunomodulators, addressing MDR by inducing apoptosis, necrosis, autophagy, and pyroptosis, enhancing anti-tumour immunity. The degradation products that are biocompatible, such as acids and alcohols, promote immune interaction within the Tumour Microenvironment (TME). The review examines the synthesis, characterization, and applications of POEs in post-surgical chemotherapy, ocular oncology, and protein delivery, as well as their interactions with cancer cell membranes and modulation of the TME. Issues such as scalability in manufacturing, enduring biocompatibility, and regulatory challenges are tackled, along with POEs’ promise in immunotherapy and gene editing for tailored medicine. Through the integration of these insights, we emphasize POEs as a symbol of optimism for targeted, less harmful cancer therapies, leading to groundbreaking oncology advancements.