A drug reservoir strategy for long-acting cancer therapy using morphologically transformed amphiphilic polymeric...

The effective accumulation of drugs within tumor tissues is impeded by extracellular barriers, necessitating repeated dosing in cancer therapy. However, repeated dosing can trigger the accelerated blood clearance (ABC) effect, resulting in limited therapeutic efficacy. Herein, in this study, a drug reservoir strategy was proposed to solve this dilemma, using an amphiphilic polymer (LPHF) with tunable hydrophilicity and morphology transformation capabilities. At pH 7.4, LPHF with balanced hydrophilicity can self-assemble into nanoparticles and be loaded with Dox (LPHF@Dox). At pH 6.5, LPHF@Dox with reduced hydrophilicity undergoes an immediate transition from a dispersed state to a deposited state, which can serve as a tumor-specific drug reservoir. Under the weakly acidic tumor microenvironment, the amide with adjacent carboxylic acid groups in LPHF exhibits pH-dependent hydrolysis, leading to a reversion of LPHF to a hydrophilic state and reconstitution into nanoparticles (LPHF@Dox_RC). The resulting LPHF@Dox_RC undergoes charge reversal to a positive state, which coordinated with conjugated folic acid, to synergistically improves both the cellular internalization and tumor penetration of LPHF@Dox_RC. This intelligent amphiphilic polymer, functioning as a tumor-specific drug reservoir, may provide a new approach for effective cancer treatment. STATEMENT OF SIGNIFICANCE: This study introduces a pH-responsive polymeric nanoparticle (LPHF) that transforms into a tumor-specific drug reservoir under acidic conditions, addressing the challenge of repeated dosing in cancer therapy. Unlike conventional systems, LPHF deposits directly in tumors via pH-triggered hydrophobicity changes. As the tumor microenvironment hydrolyzes LPHF, it releases reconstituted nanoparticles with positive charges, enhancing cellular uptake and deep tumor penetration. This dual-phase strategy-localized drug retention followed by controlled release-significantly reduces side effects and improves therapeutic efficacy. By combining material innovation with biological insights, this work offers a promising approach for long-acting cancer treatment, potentially minimizing dosing frequency. Its interdisciplinary design bridges chemistry and biomedicine, appealing to researchers and students interested in smart drug delivery and sustainable healthcare solutions.