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Recent Advances in Doxorubicin Formulation to Enhance Pharmacokinetics and Tumor Targeting
Jihoon Lee1, Min-Koo Choi2, Im-Sook Song1
1BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea.
Abstract:
Doxorubicin (DOX), a widely used drug in cancer chemotherapy, induces cell death via multiple intracellular interactions, generating reactive oxygen species and DNA-adducted configurations that induce apoptosis, topoisomerase II inhibition, and histone eviction. Despite its wide therapeutic efficacy in solid tumors, DOX often induces drug resistance and cardiotoxicity. It shows limited intestinal absorption because of low paracellular permeability and P-glycoprotein (P-gp)-mediated efflux. We reviewed various parenteral DOX formulations, such as liposomes, polymeric micelles, polymeric nanoparticles, and polymer-drug conjugates, under clinical use or trials to increase its therapeutic efficacy. To improve the bioavailability of DOX in intravenous and oral cancer treatment, studies have proposed a pH- or redox-sensitive and receptor-targeted system for overcoming DOX resistance and increasing therapeutic efficacy without causing DOX-induced toxicity. Multifunctional formulations of DOX with mucoadhesiveness and increased intestinal permeability through tight-junction modulation and P-gp inhibition have also been used as orally bioavailable DOX in the preclinical stage. The increasing trends of developing oral formulations from intravenous formulations, the application of mucoadhesive technology, permeation-enhancing technology, and pharmacokinetic modulation with functional excipients might facilitate the further development of oral DOX.
Insights
Doxorubicin (DOX) chemotherapy faces challenges with drug resistance and toxicity. New oral formulations aim to improve DOX delivery and efficacy by enhancing intestinal absorption and reducing side effects.
Area of Science:
- Pharmacology
- Oncology
- Drug Delivery
Background:
- Doxorubicin (DOX) is a vital chemotherapy agent for solid tumors, inducing apoptosis through reactive oxygen species and DNA interactions.
- However, DOX efficacy is limited by acquired drug resistance and cardiotoxicity, alongside poor oral bioavailability due to low intestinal permeability and P-glycoprotein efflux.
- Current parenteral formulations like liposomes and nanoparticles aim to enhance therapeutic index, but oral administration remains a significant challenge.
Purpose of the Study:
- To review advancements in Doxorubicin (DOX) formulations, focusing on strategies to overcome resistance and toxicity.
- To explore the development of orally bioavailable DOX formulations for improved cancer treatment.
- To identify key technologies facilitating the transition from intravenous to oral DOX delivery.
Main Methods:
- Review of existing literature on parenteral Doxorubicin (DOX) formulations (liposomes, micelles, nanoparticles, conjugates).
- Analysis of strategies for enhancing oral bioavailability, including pH/redox-sensitive systems, receptor targeting, mucoadhesiveness, and tight-junction modulation.
- Evaluation of preclinical approaches for P-glycoprotein (P-gp) inhibition and enhanced intestinal permeability.
Main Results:
- Parenteral DOX formulations have shown promise in clinical trials for improving efficacy.
- pH/redox-sensitive and targeted systems are being developed to overcome DOX resistance and reduce toxicity.
- Preclinical studies demonstrate the potential of mucoadhesive and permeation-enhancing strategies for oral DOX delivery.
Conclusions:
- Developing orally bioavailable Doxorubicin (DOX) formulations is a key trend to improve cancer therapy.
- Mucoadhesive technology, permeation enhancement, and P-gp inhibition are crucial for successful oral DOX delivery.
- Functional excipients and pharmacokinetic modulation will likely drive the future development of oral DOX formulations.
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