Recent advancement in polymeric nanoparticles for oral chemotherapy: Transforming cancer treatment

Abstract

Oral chemotherapy offers an attractive alternative to conventional intravenous administration by providing high patient compliance and improved treatment adherence. However, several challenges, like poor drug solubility, enzymatic degradation, and extensive first-pass metabolism, have significantly limited the oral bioavailability of chemotherapeutic agents. Recently, polymeric nanoparticles (PNPs) have become an alternative strategy to overcome these challenges and revolutionize the oral chemotherapeutic approach. PNPs offer unique advantages, including drug protection from harsh gastrointestinal conditions, controlled release profiles, and enhanced mucosal adhesion, which collectively improve drug absorption and therapeutic efficacy. Additionally, surface-modified PNPs can bypass efflux transporters such as P-glycoprotein and promote receptor-mediated endocytosis to achieve targeted delivery and minimize systemic toxicity. While these advancements highlight the transformative potential of PNPs in oral chemotherapy, potential clinical challenges such as scalability, reproducibility, and regulatory hurdles must be addressed to enable successful clinical translation. The present review comprehensively explores the role of PNPs in enhancing the oral delivery of cancer therapeutics, emphasizing strategies to improve drug stability, prolong gastrointestinal retention, and facilitate efficient cellular uptake. The advancements discussed herein underscore the transformative potential of PNPs as a pivotal approach for improving oral chemotherapy outcomes and expanding therapeutic possibilities in cancer management.

Introduction

Cancer remains one of the most significant global health challenges, posing a substantial burden on health care systems and patients worldwide.1 Despite extensive research and advancements in treatment modalities, cancer remains a leading cause of mortality globally.2 Among the various therapeutic strategies available, chemotherapy has remained the primary method for cancer treatment. Chemotherapy employs cytotoxic drugs to eliminate rapidly dividing cancer cells and inhibits cancer progression.3 However, traditional chemotherapy administration, predominantly through intravenous routes, presents several limitations that impact patient outcomes and quality of life.4 Intravenous (IV) chemotherapy, though effective in delivering drugs directly into the bloodstream, requires frequent hospital visits, invasive procedures, and strict medical supervision. This increases healthcare costs and imposes considerable physical and emotional stress on patients.5,6 Furthermore, intravenous administration often leads to non-specific drug distribution, which can result in severe side effects such as myelosuppression, gastrointestinal disturbances, alopecia, and organ damage.7,8 These adverse effects substantially reduce patient adherence to treatment regimens that ultimately affect the therapeutic outcomes.9

Oral chemotherapy has emerged as a promising alternative that offers numerous advantages over traditional intravenous administration. Oral administration enhances patient comfort by eliminating the need for invasive procedures, which reduces hospital visits and treatment-related stress. Additionally, oral chemotherapy facilitates long-term treatment regimens, which are particularly helpful in managing chronic cancers that require prolonged maintenance therapy. Improved patient adherence can come from better convenience and self-administration that further supports the potential of oral chemotherapy to improve clinical outcomes.10,11 However, it is crucial to emphasize that patient acceptance plays a pivotal role in the success of oral chemotherapy. Even if oral delivery achieves 100% bioavailability, the approach remains systemic in nature, and therapeutic efficacy will only improve if the encapsulated drug successfully enters systemic circulation and reaches the tumor site.12,13

Without targeted delivery, oral administration may not necessarily reduce off-target effects or enhance treatment outcomes. Despite these advantages, the oral route for chemotherapy delivery faces considerable challenges that limit its widespread application. Many chemotherapeutic agents exhibit poor aqueous solubility, which impairs their dissolution and absorption in the gastrointestinal tract (GIT).14 Furthermore, some drugs, after oral administration, often encounter significant enzymatic degradation in the GIT, which reduces their stability and bioavailability.15 The presence of efflux transporters such as P-glycoprotein (P-gp) and metabolic enzymes like cytochrome P450 enzymes reduces the drug absorption from the GIT.16 Additionally, the oral route is associated with hepatic first-pass metabolism, where drugs undergo extensive metabolic degradation in the liver before reaching the bloodstream, which further reduces their bioavailability and therapeutic efficacy.17 As a result, innovative strategies are required that can circumvent biopharmaceutical challenges.

Nanoparticles (NPs) have emerged as promising tools in pharmacology and medicine that enable targeted and efficient drug delivery. Their nanoscale size, high surface area, and tunable surface properties allow for improved drug stability, controlled release, and improved tissue distribution.18,19 Over the last three decades, various types of NPs have been explored for drug delivery applications. Among these, polymeric nanoparticles (PNPs), whether derived from natural or synthetic polymers, offer unique advantages such as biodegradability, biocompatibility, ease of functionalization, and the ability to modulate drug release profiles.

PNPs have shown promise as a viable strategy to circumvent these challenges and revolutionize oral chemotherapy. PNPs are nanoscale carriers composed of biodegradable and biocompatible polymers capable of encapsulating chemotherapeutic agents within their polymeric matrix. The encapsulation of chemotherapeutic drugs in the polymeric matrix protects the entrapped drugs from the harsh gastrointestinal (GI) environment, prevents their premature degradation, and enhances their stability.20 Furthermore, PNPs can be engineered to improve drug solubility, facilitate controlled drug release, and enhance mucosal adhesion, all of which promote better drug absorption from the GIT. A high surface-tovolume ratio due to the nanometric size of PNPs further improves their potential to traverse the mucosal barrier and enhance drug absorption, thereby improving oral bioavailability.21,22 Furthermore, the surface of PNPs can be engineered with PEG or targeting ligands that can inhibit efflux transporters like P-gp, and increase intracellular trafficking by receptor-mediated endocytosis that ultimately results in enhanced therapeutic outcomes with reduced systemic cytotoxicity.23,24

This article aims to deliver a holistic perspective on the role of PNPs in revolutionizing the oral delivery of cancer therapeutics. It will highlight different types of PNPs for oral chemotherapy, explore their mechanisms for overcoming biological as well as pharmaceutical barriers, and discuss their ability to enhance drug stability, oral bioavailability, and therapeutic outcomes. By delving into these fundamental aspects, this review strives to elucidate the significance of oral PNPs as a transformative approach for improved therapeutic outcomes with reduced systemic toxicity.

Pharmacokinetic journey of orally administered drugs

The journey of an orally administered drug begins in the mouth and follows a well-established pathway described by the ADME process: Absorption, Distribution, Metabolism, and Excretion.25 This pathway determines the drug’s pharmacokinetic profile, which in turn influences its therapeutic effectiveness. A general pharmacokinetic journey of the drug after oral administration is diagrammatically illustrated in Fig. 1. After ingestion, the drug must first dissolve in the fluids of the GI tract to be absorbed. This typically occurs in the small intestine, which has a large surface area and a rich blood supply, which makes it the primary site for absorption.26 The drug crosses the intestinal wall either by passive diffusion (moving from high to low concentration) or active transport (requiring energy and specific transport proteins).27 Once absorbed, the drug enters the portal circulation and is transported directly to the liver, where it may undergo first-pass metabolism. This process can significantly reduce the amount of active drug reaching the rest of the body.28 After passing through the liver, the drug enters the systemic circulation and is distributed throughout the body to various tissues and organs.29 The extent of distribution depends on factors such as blood flow, how easily the drug can pass through tissue barriers (permeability), and how much of the drug binds to proteins in the blood.30

Next, the drug is metabolized, primarily in the liver, through phase I (modification) and phase II (conjugation) reactions. These chemical changes are carried out by enzymes, most notably those from the cytochrome P450 family, and can convert the drug into either active or inactive forms.31,32 Finally, the drug and its metabolites are excreted from the body. The kidneys play a major role, filtering the blood and eliminating substances through urine. Other excretion routes include bile (from the liver to the intestines), the lungs (exhalation), and secretions such as sweat or saliva.33 Together, these processes determine the drug’s bioavailability (how much of it reaches the bloodstream), half-life (how long it stays in the body), and overall therapeutic effect.

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Table 1. Comparative analysis of different PNPs for oral chemotherapy

Karthik Mangu , Ruhan Gudeli, Md. Rizwanullah, Recent advancement in polymeric nanoparticles for oral chemotherapy: Transforming cancer treatment, Mangu et al., BioImpacts. 2025;15:31117, doi: 10.34172/bi.31117, https://bi.tbzmed.ac.ir/