Institute of Pharmaceutical Education and Research, Borgaon Meghe, Wardha.
Cancer remains one of the foremost causes of global mortality, primarily driven by intricate genetic, epigenetic, and tumor microenvironmental alterations that facilitate uncontrolled cellular proliferation and disease progression. Despite notable progress in conventional treatment approaches such as chemotherapy, radiotherapy, and surgical intervention, their clinical efficacy is often constrained by systemic toxicity, limited tumor selectivity, and the development of therapeutic resistance. In this regard, nanotechnology-based drug delivery systems have emerged as a promising and innovative strategy to improve the precision and effectiveness of cancer therapy. This review presents a succinct overview of major cancer types, including breast, gastric, pancreatic, oral, prostate, colorectal, thyroid, and gallbladder cancers, with a focus on their cellular and molecular pathophysiology. Fundamental oncogenic mechanisms such as genomic instability, dysregulation of the cell cycle, resistance to apoptosis, aberrant signaling cascades, and epigenetic alterations are discussed to provide insight into tumor initiation and progression. Furthermore, the review emphasizes recent developments in nanoparticle-based drug delivery systems, including liposomes, dendrimers, gold nanoparticles, magnetic nanoparticles, quantum dots, mesoporous silica nanoparticles, and carbon nanotubes. The role of physicochemical properties such as particle size, surface modification, and elasticity in influencing biodistribution, tumor penetration, cellular uptake, and controlled drug release is critically evaluated. Targeting strategies, including passive targeting through the enhanced permeability and retention effect and active targeting via ligand–receptor interactions, are also examined. Collectively, nanotherapeutic approaches demonstrate strong potential to address the limitations of conventional cancer therapies and enhance clinical outcomes in oncology.
Cancer remains one of the leading causes of mortality worldwide. Although advancements in treatment modalities and the development of drug delivery systems have reduced mortality rates, achieving a complete cure remains a significant challenge. Treatment strategies are largely stage-dependent, necessitating tailored therapeutic approaches. In recent decades, nanotechnology-based drug delivery systems have emerged as a promising alternative to conventional chemotherapy. Unlike traditional chemotherapeutic agents, which often damage both cancerous and healthy cells, nano drugs enable targeted delivery, enhancing therapeutic efficacy while minimizing systemic toxicity. This approach offers better control over how and where drugs are released over time, transforming the landscape of cancer research with its ability to deliver drugs with unmatched accuracy and minimal side effects[1].
The process of manufacturing nano drugs is in general called nanonization. In the nanonization process, drug particles are reduced to sizes between 1 and 100 nm and encapsulated in various delivery systems like nanoparticles, liposomes, or micelles.
Cancer remains a leading cause of global mortality, necessitating the development of more effective and targeted therapeutic strategies. Conventional treatment modalities such as chemotherapy, radiotherapy, and surgery are often associated with significant limitations, including systemic toxicity, non-specific distribution, and the development of multidrug resistance. In this context, nanotechnology has emerged as a transformative approach in oncology, enabling the design of advanced drug delivery systems with improved specificity and therapeutic efficiency[2].
Nanoparticles offer unique physicochemical properties, including tunable size, surface functionality, and high drug-loading capacity, which facilitate enhanced tumor targeting and controlled drug release. These systems can exploit passive targeting mechanisms such as the enhanced permeability and retention (EPR) effect, as well as active targeting through ligand–receptor interactions. Furthermore, the development of stimuli-responsive or “smart” nanoparticles allows drug release to be triggered by internal factors such as pH, enzymes, and redox conditions, or external stimuli including light, temperature, and magnetic fields[3].
Recent advances have also focused on overcoming biological barriers associated with the tumor microenvironment (TME), such as abnormal vasculature, dense extracellular matrix, and elevated interstitial pressure, which limit effective drug penetration. Additionally, multifunctional nanoplatforms integrating chemotherapy, gene therapy, immunotherapy, and diagnostic capabilities have shown significant potential in improving therapeutic outcomes. Emerging strategies such as subcellular targeting further enhance treatment efficacy by delivering therapeutic agents directly to specific organelles within cancer cells[4].
Despite these advancements, challenges related to delivery efficiency, safety, and clinical translation remain. Therefore, continued research is essential to optimize nanoparticle design and develop next-generation nanomedicines for precision oncology [5].
2. Cancer
Cancer is a genetic disorder characterized by genomic instability, involving the accumulation of mutations and structural DNA alterations during tumor progression. It arises from normal human cells that undergo transformation and evade regulatory control, contributing to tumor development. Tumor growth and survival are strongly influenced by changes in the tissue microenvironment and chronic inflammation. Advances in technologies such as next-generation sequencing, multi-omics, and single-cell analysis have significantly improved the understanding of cancer biology. Precision medicine recognizes tumor heterogeneity and tailors treatment based on genetic, environmental, and lifestyle factors. Chronic inflammation is associated with several cancers, including colorectal, liver, and gastric cancers, while therapy resistance remains a major challenge in effective cancer treatment [6].
2.1 Various Types of Cancer [7]
Fig No.1: Representation of various types of cancer
2.1.1 Breast Cancer
Breast cancer is one of the most common malignant tumors in women, influenced by genetic and environmental factors. Virchow (1863) linked cancer to chronic inflammation, now known to contribute to tumor development through cytokines (TNF, IL-1), chemokines (CCL2, CXCL8), leukocyte infiltration, tissue remodeling, and angiogenesis. Tumor-associated macrophages play a key role in this process. Breast cancer is classified into molecular subtypes such as basal-like, Luminal A, Luminal B, and HER2-enriched, guiding treatment strategies. Hormone receptor-positive (ER/PR+) HER2-negative cases are mainly treated with hormonal therapy, while chemotherapy options include taxanes, anthracyclines, and platinum agents. Incidence increases with age, especially between 50–69 years.
2.1.2 Gastric Cancer
Gastric cancer is primarily gastric adenocarcinoma, classified into cardia and non-cardia types. Risk factors include smoking and alcohol consumption. Treatment involves surgery as the primary approach for localized disease, with chemotherapy, radiotherapy, targeted therapy, and immunotherapy used as adjuvant or neoadjuvant options to improve outcomes.
2.1.3 Pancreatic Cancer
Pancreatic cancer is often diagnosed at an advanced stage and has poor prognosis due to therapeutic resistance. Incidence is increasing with aging populations and rising obesity rates. Risk factors include smoking, diabetes mellitus, pancreatitis, alcohol intake, BMI, allergies, and microbiome alterations. Metabolic dysfunction-associated steatotic liver disease (MASLD) is also associated with metabolic risk conditions relevant to pancreatic inflammation.
2.1.4 Oral Cancer
Oral cancer is a subset of head and neck cancers, predominantly squamous cell carcinoma. It affects oral cavity and oropharyngeal regions, often associated with HPV infection, tobacco, and alcohol use. Early-stage detection improves prognosis, but asymptomatic progression delays diagnosis. It significantly impacts speech, mastication, swallowing, and quality of life. Incidence is higher in males aged 50–70, though younger cases are increasing.
2.1.5 Prostate Cancer
Prostate cancer arises in the prostate gland, commonly in older males. Risk factors include genetics, family history, and socioeconomic status. Diagnosis has improved with PSA testing, mpMRI, and PSMA PET/CT imaging. Treatment includes radical prostatectomy (first described in 1905), radiation, and active surveillance, with selection based on patient condition and disease stage.
2.1.6 Gallbladder Cancer
Gallbladder cancer is a highly lethal malignancy often diagnosed late, commonly associated with gallstones and chronic inflammation. It is classified under biliary tract cancers. Risk factors include obesity, gallstones, dietary habits, and chronic gallbladder inflammation. Early awareness and preventive strategies are essential for reducing incidence and improving prognosis.
2.1.7 Colorectal Cancer
Colorectal cancer is the third most common cancer globally and a leading cause of cancer mortality. It includes colon and rectal cancers, with metastasis commonly affecting liver and lungs. Males show higher incidence and mortality. Carcinoembryonic antigen (CEA) is widely used for monitoring disease progression, though it lacks specificity. Prognosis varies by stage and population demographics.
2.1.8 Thyroid Cancer
Thyroid cancer is the most common endocrine malignancy, originating from follicular or parafollicular cells. Follicular-derived cancers include papillary (80–85%), follicular (10–15%), poorly differentiated (<2%), and anaplastic (<2%) types. Management includes surgery, radioactive iodine, and TSH suppression. Risk factors include radiation exposure, age, sex, genetics, and environmental influences.
2.1.9 Ovarian Cancer
Ovarian cancer is a relatively less common gynecological malignancy compared to uterine cancer. It often presents late due to non-specific symptoms, leading to poor prognosis and reduced survival rates.
2.2 Cellular and Molecular Pathophysiology of Cancer [8]
Cancer is a complex and multifactorial disease characterized by uncontrolled cell proliferation that arises from the accumulation of genetic, epigenetic, and microenvironmental alterations. At the cellular and molecular levels, cancer progression is associated with the disruption of normal regulatory systems responsible for controlling cell growth, differentiation, survival, and maintenance of genomic integrity.
2.2.1 Genetic Alterations and Genomic Instability
At the molecular level, cancer initiation is primarily driven by genetic mutations affecting critical regulatory genes, including oncogenes, tumor suppressor genes, and DNA repair genes. The activation of oncogenes such as RAS, MYC, and HER2 leads to sustained cell proliferation through enhanced growth factor signaling pathways. Conversely, the loss or inactivation of tumor suppressor genes such as TP53, RB1, and PTEN eliminates essential cell cycle checkpoints, allowing abnormal cells with genetic damage to survive and proliferate.Genomic instability is a defining characteristic of cancer cells and is mainly caused by defects in DNA repair mechanisms. Impairment of mismatch repair, homologous recombination, or nucleotide excision repair pathways results in the progressive accumulation of mutations, chromosomal abnormalities, and aneuploidy, thereby contributing to tumor development and progression.
2.2.2 Dysregulation of Cell Cycle and Apoptosis
Under normal physiological conditions, cell cycle progression is strictly regulated by cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. In cancer cells, these regulatory mechanisms become disrupted, leading to uncontrolled and continuous cell division. Overexpression of cyclins and CDKs, along with decreased levels of CDK inhibitors, promotes persistent progression through the S and M phases of the cell cycle. In parallel, cancer cells acquire the ability to evade programmed cell death (apoptosis). This is achieved through the increased expression of anti-apoptotic proteins such as BCL-2 and BCL-XL, along with suppression of pro-apoptotic proteins including BAX and BAK. As a result, cells that should normally undergo apoptosis due to DNA damage are able to survive and continue proliferating.
2.2.3 Altered Cellular Signaling Pathways
Dysregulated intracellular signaling pathways play a central role in cancer pathophysiology. Major pathways, including PI3K/AKT/mTOR, MAPK/ERK, and Wnt/β-catenin, become constitutively activated, leading to enhanced cellular proliferation, survival, and metabolic adaptation. These signaling pathways also regulate processes such as cell migration and invasion, thereby contributing to tumor growth and metastatic spread. Interactions, or crosstalk, between these signaling networks further intensify oncogenic signaling, resulting in the formation of a self-sustaining system that supports malignant transformation and promotes resistance to therapy.
2.2.4 Epigenetic Modifications
In addition to genetic mutations, epigenetic alterations significantly contribute to cancer development. Changes in DNA methylation patterns, histone modifications, and chromatin structure can lead to the silencing of tumor suppressor genes or activation of oncogenes without altering the underlying DNA sequence. Global DNA hypomethylation is associated with chromosomal instability, whereas localized hypermethylation in promoter regions leads to suppression of genes involved in cell cycle regulation and apoptosis. Importantly, epigenetic alterations are potentially reversible, which makes them promising targets for therapeutic intervention in cancer management.
3. Nanoparticles
Nanoparticles (NPs) are advanced drug delivery systems designed for targeted cancer therapy, particularly in solid tumors. They improve pharmacokinetics, biodistribution, and tumor targeting, enhancing therapeutic efficacy while reducing side effects. However, clinical outcomes remain limited, as survival benefits are not consistently significant. Drug delivery efficiency depends on systemic processes after intravenous administration, including circulation, tumor targeting, penetration, cellular uptake, and controlled drug release. Recent research also highlights the importance of nanoparticle mechanical properties in influencing biological interactions and therapeutic performance [9].
3.1 Advantages of Nanoparticles (NPs)[10]
3.2 Disadvantages of Nanoparticles (NPs)[10]
3.3 Characterization of nanoparticle mechanical properties[9]
Mechanical properties of NPs are mainly characterized using parameters such as elastic modulus, stiffness, and Young’s modulus.
Young’s modulus is widely used to quantify the ability of nanoparticles to resist mechanical deformation.
Atomic force microscopy (AFM) is the most commonly used technique for measuring nanoparticle mechanical properties.
The Hertz model and Sneddon model are applied to calculate Young’s modulus from experimental data.
Bending rigidity is an important parameter used to evaluate membrane deformation and nanoparticle wrapping in biological systems.
3.4 Design and development of nanotherapeutics[11]
The design and development of precisely targeted therapeutic drugs are crucial for effective cancer imaging and treatment. Due to the complex nature of the tumor microenvironment (TME), single-agent therapy targeting a specific cellular or molecular component is often insufficient for effective cancer management. In contrast, conventional cancer treatments are associated with significant adverse effects, which has driven the development of multifunctional nanotherapeutics for a more comprehensive treatment approach.
The development of TME-targeted therapeutics requires understanding of optimal in vivo behavior, interactions between therapeutic agents and biological systems, pathological features of the TME, and the properties of drugs that enable effective targeting. It also involves selection and combination of therapeutic agents for multimodal treatment strategies. Various carrier systems, including liposomes, micelles, polymeric conjugates, dendrimers, inorganic nanoparticles, and biological vectors such as viruses and cell-based systems, have been engineered to deliver drugs, genes, or photosensitizers for chemotherapy, gene therapy, and photodynamic therapy. These systems improve therapeutic efficiency compared to conventional small-molecule drugs. However, challenges remain in developing delivery systems that are precisely optimized at molecular and cellular levels while ensuring effective in vivo performance.
3.5 Influence of nanoparticle mechanical properties on cancer drug delivery process[12]
3.5.1 Blood Circulation
Prolonged blood circulation is a major challenge for intravenously administered nanomedicines due to biological barriers such as opsonization, the reticuloendothelial system (RES), and blood filtration. Surface modifications like PEGylation are commonly used to reduce clearance and extend circulation time. Recently, mechanical properties have gained attention, where softer nanoparticles generally exhibit longer circulation times than stiffer ones, as macrophage uptake is inversely related to blood persistence.
3.5.2 Biodistribution and Tumor Accumulation
Effective nanomedicine delivery depends on the distribution of nanoparticles across organs and tumor tissues. Uptake by the liver and spleen often reduces circulation time and tumor targeting efficiency. Modulation of mechanical properties has been shown to influence biodistribution and improve tumor accumulation of nanomedicines by reducing premature clearance and enhancing systemic stability.
3.5.3 Deep Tumor Penetration
Penetration into solid tumors is essential for therapeutic efficacy, but is hindered by abnormal tumor vasculature, dense extracellular matrix (ECM), and high interstitial pressure. Mechanical properties significantly affect penetration ability. Studies using 3D tumor spheroids show that softer nanoparticles penetrate more deeply into tumor structures compared to stiffer nanoparticles, indicating improved intratumoral distribution.
3.5.4 Cellular Internalization
Efficient uptake by tumor cells is a critical step in drug delivery. The effect of nanoparticle stiffness on cellular internalization is complex. While macrophages tend to prefer stiffer nanoparticles, tumor cells may exhibit higher uptake of either stiff or soft nanoparticles depending on the system. Some studies report greater uptake of stiffer nanoparticles, while others show enhanced internalization with softer formulations.
3.5.5 Drug Release
Mechanical properties also influence drug release behavior. In some systems, softer nanoparticles enable faster drug release and improved therapeutic response due to rapid uptake and intracellular release. However, in other cases, no significant difference in release profiles is observed between soft and stiff nanoparticles, indicating that release behavior is formulation-dependent.
4. Nanoparticles in a cancer therapy mechanistic insights and drug delivery strategies
Nanoparticles play a crucial role in modern cancer therapy by significantly improving drug delivery performance, therapeutic targeting, and overall treatment efficiency through a variety of advanced mechanisms and material platforms.
4.1 Liposomes (Active targeting strategies): Liposomal drug delivery systems enhance passive targeting by prolonging systemic circulation through PEGylation, which forms a hydration layer that reduces recognition and clearance by the immune system. This allows improved accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect. In addition to passive targeting, active targeting is achieved by functionalizing liposomes with ligands such as transferrin receptor (TfR) and folate receptor (FR), which are overexpressed on many cancer cells. These ligand-conjugated systems promote receptor-mediated endocytosis, enhancing intracellular drug delivery, increasing antitumor activity, and reducing systemic toxicity. They also help overcome multidrug resistance by bypassing efflux mechanisms such as P-glycoprotein, improving the therapeutic outcome of drugs like doxorubicin[13].
4.2 Dendrimers in cancer therapy: Dendrimers are highly branched nanocarriers that offer controlled architecture, high drug-loading capacity, and excellent biocompatibility. They improve drug solubility, circulation time, and targeted delivery efficiency. Both covalent drug conjugation and non-covalent encapsulation are possible, making them versatile delivery systems. Dendrimers have shown strong potential in delivering hydrophobic anticancer agents such as camptothecin derivatives, significantly enhancing their therapeutic efficacy. Studies demonstrate that dendrimer-based formulations improve cellular uptake, reduce toxicity, and increase anticancer activity against various cancer cell lines, including breast and colon cancer. Their ability to provide controlled and targeted release further reduces systemic side effects compared to free drugs.
4.3 Gold nanoparticles (Au-NPs): Gold nanoparticles are widely used in cancer nanomedicine due to their stability, biocompatibility, and ease of surface modification. They serve as effective carriers for drugs, genes, and biologically active molecules. Au-NP-based systems enhance tumor targeting and reduce off-target effects by enabling conjugation with therapeutic agents such as tumor necrosis factor-alpha (TNF-α) and methotrexate. PEG-coated Au-NPs improve circulation time and minimize immune clearance, while also enhancing antiangiogenic effects and tumor growth inhibition. Additionally, gold nanoparticles have been used in multifunctional systems combining chemotherapy and targeted therapy, showing improved tumor suppression with reduced systemic toxicity. Their surface can also be engineered for controlled drug release using external stimuli such as light or heat[14].
4.4 Magnetic nanoparticles (MNPs): Magnetic nanoparticles function as both drug carriers and therapeutic agents, particularly in magnetic hyperthermia. When exposed to an alternating magnetic field (AMF), they generate localized heat through hysteresis loss and relaxation processes, leading to selective tumor cell destruction. This hyperthermia effect disrupts cellular proteins, increases membrane permeability, and induces apoptosis in cancer cells while sparing surrounding healthy tissues. MNPs are also used to enhance chemotherapy and radiotherapy effectiveness by sensitizing tumor cells to treatment. However, careful control is required to minimize non-specific heating and potential damage to normal tissues[15].
4.5 Quantum dots (QDs): Quantum dots are advanced fluorescent nanoprobes used primarily for imaging and diagnostic applications in cancer research. They exhibit high photostability and strong fluorescence, allowing long-term tracking of biological processes. QDs can be conjugated with biomolecules for intracellular and cell-surface labeling, enabling precise visualization of tumor cells. They are also used for nuclear imaging and real-time tracking of molecular transport without significant cytotoxic effects, making them valuable tools in cancer diagnostics and mechanistic studies.
4.6 Mesoporous silica nanoparticles (MSNs): Mesoporous silica nanoparticles are highly efficient drug delivery systems due to their large surface area, tunable pore size, and excellent stability. They improve the solubility and bioavailability of poorly water-soluble anticancer drugs such as paclitaxel and camptothecin. MSNs also allow controlled drug loading and release, enhancing therapeutic efficiency while reducing systemic toxicity. Their surface can be modified for targeted delivery, making them suitable for combination therapy approaches[16].
4.7 Carbon nanotubes (CNTs): Carbon nanotubes are promising nanocarriers due to their high surface area, structural strength, and ability to penetrate biological membranes. Functionalized CNTs can transport drugs, genes, and peptides into cancer cells via endocytosis, enabling targeted drug delivery. They improve drug loading capacity and prolong circulation time, enhancing tumor accumulation through the EPR effect. CNT-based systems have demonstrated improved efficacy in delivering chemotherapeutic agents like paclitaxel and gemcitabine, particularly in targeted cancer and lymphatic delivery systems. Their ability to overcome multidrug resistance and reduce systemic toxicity makes them valuable in advanced cancer nanotherapy[17].
Fig No. 2: Nanotherapeutics in cancer[18]
5. Challenges
Despite promising advancements, nanoparticle-based cancer therapy faces several critical challenges. The low delivery efficiency in vivo remains a major limitation, as nanoparticles are rapidly cleared by the reticuloendothelial system and encounter multiple biological barriers before reaching tumors. The heterogeneous tumor microenvironment (TME), with dense extracellular matrix and abnormal vasculature, restricts deep tumor penetration and uniform drug distribution. Additionally, a significant gap exists between preclinical success and clinical outcomes, limiting real-world effectiveness. Concerns regarding toxicity, long-term safety, and organ accumulation also persist. Furthermore, challenges in large-scale manufacturing, reproducibility, and regulatory approval hinder clinical translation. Optimization of nanoparticle physicochemical and mechanical properties is complex, and multidrug resistance (MDR) further reduces therapeutic efficacy.
FUTURE PERSPECTIVES
Future research is expected to focus on personalized nanomedicine, where treatments are tailored based on tumor-specific and patient-specific characteristics. The development of stimuli-responsive (smart) nanoparticles will allow controlled and site-specific drug release. Multifunctional nanocarriers combining chemotherapy, gene therapy, and immunotherapy offer a promising approach to overcome tumor heterogeneity and resistance. Advances in understanding nanoparticle mechanical properties may improve circulation time, tumor penetration, and cellular uptake. Moreover, the application of artificial intelligence (AI) can accelerate nanoparticle design and optimize therapeutic outcomes. Establishing standardized models and regulatory guidelines will be essential for successful clinical translation.
CONCLUSION
Nanoparticle-based drug delivery systems have emerged as a powerful strategy in cancer therapy, providing improved targeting, enhanced efficacy, and reduced systemic toxicity. However, several biological and translational challenges remain unresolved. With continued advancements in nanotechnology, interdisciplinary approaches, and rigorous clinical validation, nanomedicine holds strong potential to revolutionize cancer treatment and significantly improve patient outcomes.
REFERENCES
Gunjan Joshi, Durgesh Thakare, Ketan Warbhe, Ankit Kediya, Madhura Masane, Sanika Shende, Rohit Girhepunje, Next-Generation Nanomedicine in Cancer Therapy: Mechanistic Insights, Delivery Challenges, and Multifunctional Targeting Approaches, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 2783-2793, https://doi.org/10.5281/zenodo.20133693
10.5281/zenodo.20133693
