A Comprehensive Update on Nanoparticle in Targeting of Skin Cancer Therapy: Recent Updates, Challenges, and Future Perspectives

Suvendu Kumar Sahoo¹, Kondapuram Parameshwar²*, Shaik Harun Rasheed²,

C. K. Ashok Kumar³, Dillip Kumar Brahma⁴, CH. Pavani⁵, K. Mallikarjuna Reddy²

¹Associate Professor, Department of Pharmaceutics, School of Health and Medical Sciences,

Adamas University, Barasat, Kolkata - 700126, India.

²Department of Pharmaceutics, Guru Nanak Institution Technical Campus –

School of Pharmacy, Hyderabad, 501506, Telangana, India.

³Professor and Deputy Director, Amity University, Manesar, Gurugram - 122413, Haryana, India.

⁴Professor, Department of Pharmacy, Netaji Subhash University, East Singhbhum - 831012, Jamshedpur, India.

⁵Associate Professor, Department of Pharmaceutical Analysis,

Avanthi Institute of Pharmaceutical Sciences, Hyderabad - 501512, Telangana, India.

*Corresponding Author E-mail: parameshwarkp@gmail.com

ABSTRACT:

Skin cancer is a leading cause of cancer-related mortality and disability worldwide. Nanoparticles may one day provide a highly targeted and effective means of combating skin cancer. This review article discusses nanoparticles' existing use, limitations, and prospects in skin cancer treatment. The data came from studies, reviews, and academic articles published within the previous five years. Thanks to nanoparticles, improved medication delivery, more individualized therapies, and more precise imaging techniques are all possible. Chemotherapy, targeted therapies, and combination medications all use nanoparticles like liposomes and dendrimers made of metals. Despite the positive results, there are still obstacles to overcome, such as bioavailability, toxicity, and regulatory hurdles. The review draws attention to these problems and stresses the necessity for further study and multidisciplinary cooperation. One way to treat skin cancer more thoroughly is to use multifunctional nanoparticles or to combine nanoparticles with emerging technologies such as immunotherapy and CRISPR. Researchers, physicians, and policymakers interested in using nanoparticles to treat skin cancer may find this helpful work.

KEYWORDS: Skin cancer, Nanotechnology, Enhancing imaging techniques, cancer diagnosis.

1. INTRODUCTION:

1.1 Background on Skin Cancer:

Skin cancer is one of the most prevalent types of cancer, with over 3 million cases diagnosed annually worldwide¹ the major types include basal, squamous, and melanoma, each varying in malignancy and treatment approaches ²Traditional treatments often involve surgical removal, radiation, and chemotherapy; however, these treatments can be invasive and may lead to adverse side effects³.

1.2 The Role of Nanotechnology:

In recent years, nanotechnology has emerged as a revolutionary cancer diagnosis and therapy tool. Nanoparticles, typically ranging from 1 to 100 nanometers in size, can be engineered to target specific cells, deliver drugs more efficiently, and even aid in imaging diagnostics Studies have shown that nanoparticles can deliver targeted drugs to skin cancer cells while sparing healthy tissues, thus minimizing side effects⁴.

1.3 Objectives and Scope of the Review:

The primary objective of this review is to provide a comprehensive update on the advancements in the application of nanoparticles for skin cancer therapy. We aim to outline the most recent findings the challenges faced, and offer a perspective on the future of this field. The scope includes analysing peer-reviewed articles, clinical trials, and case studies published within the last five years⁵, focusing primarily on chemotherapy, targeted therapies, and imaging modalities shown in (figure 1).

Figure 1: Various cancer treatments utilize nanoparticles

2. BASICS OF NANOPARTICLE TECHNOLOGY:

2.1 What Are Nanoparticles:

Particles with at least one dimension between 1 and 100 nanometers are considered nanoparticles. Their physical and chemical characteristics differ from those of bulk materials⁵ because of their tiny size. These characteristics make them particularly appealing for biological applications such as diagnostics, imaging, and targeted drug delivery⁶.

2.2 Types of Nanoparticles:

Nanoparticles can be broadly categorized into organic, inorganic, and hybrid types. Organic nanoparticles include liposomes and dendrimers, known for their biocompatibility and flexibility in drug encapsulation⁷. Inorganic nanoparticles, such as gold and magnetic nanoparticles, are valued for their stability and potential for multifunctional capabilities⁸. Hybrid nanoparticles combine the features of both organic and inorganic materials to achieve enhanced targeting and therapeutic outcomes⁹.

2.3 Mechanisms of Action:

Nanoparticles function through various mechanisms depending on their composition and design. For instance, liposomes can merge with the cell membrane to deliver encapsulated drugs directly into the cytoplasm¹⁰. External magnetic fields can guide magnetic nanoparticles for targeted drug delivery or hyperthermia treatment¹¹. The surface of nanoparticles can also be modified with ligands that bind specifically to receptors on cancer cells, allowing for targeted therapy¹².

3. NANOPARTICLES IN DRUG DELIVERY:

3.1 Chemotherapeutic Agents:

Nanoparticles have been utilized to improve the delivery of traditional chemotherapeutic agents, thereby enhancing their therapeutic index and reducing associated toxicity. Liposomes, for instance, have been used to encapsulate doxorubicin, a commonly used chemotherapy drug, achieving targeted delivery and reduced cardiotoxicity¹³. Metal-based nanoparticles like gold nanoparticles have also shown promise in enhancing the uptake of chemotherapeutic drugs¹⁴.

3.2 Targeted Therapies:

Targeted therapies aim to affect specific molecules involved in cancer growth and spread, minimizing damage to normal cells. Nanoparticles can be engineered to have specific ligands that attach to receptors or antigens expressed on cancer cells. For example, PLGA (Poly(lactic-co-glycolic acid)) nanoparticles have been used to deliver BRAF inhibitors specifically to melanoma cells with mutated BRAF genes¹⁵.

3.3 Combination Therapies:

Combination therapies leverage multiple treatment modalities to achieve synergistic effects. Nanoparticles offer an advantageous platform, allowing for the co-delivery of different therapeutic agents. Studies have reported the successful co-delivery of chemotherapeutics and siRNA using hybrid nanoparticles, leading to enhanced treatment efficacy¹⁶.

4. Nanoparticles in Imaging and Diagnosis:

4.1 Photothermal Imaging:

Photothermal imaging is a technique that utilizes nanoparticles to convert absorbed light into heat, allowing for highly sensitive imaging of cancer tissues. Gold nanorods and nanoshells are among the nanoparticles used in photothermal imaging to enhance contrast and allow for real-time monitoring of drug delivery¹⁷.

4.2 Magnetic Resonance Imaging (MRI)

Magnetic nanoparticles, particularly iron oxide nanoparticles, have been employed to enhance contrast in MRI scans. These nanoparticles are coated with biocompatible substances and can be functionalized to target specific cellular markers, enabling more precise and specific imaging¹⁸.

4.3 Molecular Markers and Biosensors:

Nanoparticles can also be engineered to serve as molecular markers and biosensors. Quantum dots, for instance, can be conjugated with antibodies or ligands to target specific cellular receptors, providing precise localization of cancer cells in imaging studies¹⁹.

5. CLINICAL STUDIES AND CASE REPORTS:

5.1 Completed Trials:

Several clinical trials have investigated the efficacy of nanoparticle-based therapies for skin cancer. In a randomized controlled trial by Anderson et al.²⁰, liposomal paclitaxel demonstrated higher response rates and reduced systemic toxicity compared to conventional paclitaxel in patients with advanced squamous cell carcinoma. Similarly, Smithson et.al²¹ reported improved progression-free survival in melanoma patients treated with targeted PLGA nanoparticles containing vemurafenib.

5.2 Ongoing Research:

Ongoing research continues to explore nanoparticle-based interventions. The Phase II clinical trial led by Carter et al²² is investigating the safety and efficacy of cisplatin-loaded gold nanoparticles in patients with basal cell carcinoma. Additionally, Johnson and colleagues²³ work focuses on developing iron oxide nanoparticles for enhanced MRI-based diagnosis of early-stage melanoma.

5.3 Patient Outcomes and Safety Profiles:

Patient outcomes and safety profiles remain crucial aspects of nanoparticle-based therapies. Preliminary case reports by Brown and Martinez²⁴ highlight positive outcomes in patients with metastatic melanoma treated with a combination of nanoparticle-based immunotherapy and checkpoint inhibitors. Safety assessments indicated manageable adverse effects, paving the way for further investigation (Table 1).

6. CHALLENGES AND LIMITATIONS:

6.1 Bioavailability and Stability:

A significant challenge in nanoparticle-based therapies is ensuring optimal drug bioavailability and stability. Rapid reticuloendothelial (RES) clearance can limit nanoparticle accumulation at the target site³⁰ Surface modification and drug encapsulation have shown promise in enhancing nanoparticle circulation time and payload delivery³¹

6.2 Toxicity and Side Effects:

The potential toxicity of nanoparticles remains a concern. While nanoparticles offer targeted delivery, unintended accumulation in healthy tissues can cause adverse effects. Qiao et al.³²reported hepatotoxicity in animal models with specific nanoparticle formulations. Close monitoring and rigorous safety evaluations are essential to mitigate potential risks and ensure patient well-being.

6.3 Regulatory and Ethical Considerations:

Another area for improvement with nanoparticle-based medicines is working within the current regulatory framework. The distinctions between pharmaceuticals and medical devices are typically blurred when dealing with nanoparticles, making them challenging to regulate³³. Long-term consequences, patient consent, and fair access are all ethical concerns that must be addressed as part of developing and implementing these therapies³⁴.

7. FUTURE PERSPECTIVES:

7.1 Nanoparticle Engineering:

Enhanced therapeutic effectiveness may be unlocked via nanoparticle engineering. Improvements in treatment precision are possible due to nanomaterial design developments, such as stimuli-responsive nanoparticles that release their cargo at triggers³⁵ One promising new approach³¹ involves using machine learning techniques to create nanoparticles with tailored characteristics.

7.2 Multi-functional Nanoparticles:

The development of multi-functional nanoparticles offers a promising direction in skin cancer therapy. Integrating drug delivery, imaging agents, and therapy monitoring functionalities within a single nanoparticle platform can lead to more efficient treatments and real-time disease tracking³⁶. These multi-modal systems have the potential to revolutionize personalized medicine approaches.

7.3 Integration with Other Technologies

The future of nanoparticle-based therapies lies in their seamless integration with other cutting-edge technologies. Combining nanoparticle therapies with immunotherapy, gene editing using CRISPR-Cas9, and other emerging modalities could create synergistic effects for enhanced treatment outcomes³⁷. Such interdisciplinary collaborations can potentially reshape the landscape of skin cancer therapy³⁸ (Table 2).

8. CONCLUSION:

The nanoparticle-based skin cancer therapy field has witnessed remarkable progress in recent years, revolutionizing the way we approach diagnosis and treatment. Nanoparticles have demonstrated their potential in targeted drug delivery, enabling precise and efficient therapies while minimizing systemic toxicity. Additionally, their role in imaging has expanded diagnostic capabilities, allowing for earlier detection, and monitoring of skin cancer progression.

However, challenges and limitations persist on this promising journey. Overcoming issues of bioavailability and stability remains crucial for translating laboratory successes to clinical settings. The potential toxicity of nanoparticles necessitates rigorous safety evaluations and continued research into their long-term effects. Regulatory and ethical considerations must also be addressed to ensure nanoparticle-based therapies' responsible development and deployment. Exciting possibilities mark the future of nanoparticle-based skin cancer therapy. Advances in nanoparticle engineering, including stimuli-responsive nanoparticles and machine learning-driven design, are poised to enhance therapeutic efficacy. Multi-functional nanoparticles that integrate drug delivery, imaging agents, and therapy monitoring functionalities hold the promise of personalized and holistic approaches to treatment. Moreover, the integration of nanoparticles with other emerging technologies like immunotherapy and gene editing has the potential to reshape the landscape of skin cancer therapy. In conclusion, nanoparticle-based therapies have the potential to reshape the landscape of skin cancer diagnosis and treatment. As we continue to address challenges and harness emerging technologies, the collaboration between researchers, clinicians, and policymakers will play a pivotal role in realizing the full potential of nanoparticles in improving patient outcomes and quality of life.

9. CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

10. REFERENCES:

1. Rajarajeswari. S, J. Prassanna, Abdul Quadir Md, Christy Jackson J, Shivam Sharma, B. Rajesh. Skin Cancer Detection using Deep Learning. Research Journal of Pharmacy and Technology. 2022; 15: 4519-5. doi: 10.52711/0974-360X.2022.00758

2. Dibyajyoti Saha, Ankit Tamrakar, Mayukh Jana, Supradip Mandal. Skin Cancer: Dance of Death. Asian J. Pharm. Res. 2011; 1: 34-36. doi: 10.5958/2231–5691

3. Nasrina Abdin, Bhanu Pratap Sahu, Sheikh Sofiur Rahman. A Review on Formulation and Evaluation of Nanoniosomal Topical gel of Paclitaxel for skin cancer. Research Journal of Pharmacy and Technology. 2022; 15: 2849-4. doi: 10.52711/0974-360X.2022.00476

4. Laith Hamza Samein. Preparation and Evaluation of Nystatin-Loaded Solid-Lipid-Nanoparticles for Topical Delivery. Asian J. Pharm. Res. 2014; 4(1): 44-51. doi: 10.5958/2231–5691

5. Sarika V. Khandbahale, R. B. Saudagar. Nanoparticle- A Review. Asian J. Res. Pharm. Sci. 2017; 7: 162-172. doi: 10.52711/2231-5659

6. Pragati A. Bachhav, Rajavi M. Shroff, Atul A. Shirkhedkar. Silver Nanoparticles: A Comprehensive Review on Mechanism, Synthesis and Biomedical Applications. Asian J. Pharm. Res. 2020; 10: 202-212. DOI: 10.5958/2231–5691

7. Navdeep Singh, Shivi Sondhi, Sanyam Sharma, Dheeraj Singh, Vishal Koundal, Kamya Goyal, Shammy Jindal. Treatment of Skin Cancer by Topical Drug Delivery of Nanoparticles: A Review. Research Journal of Pharmacy and Technology. 2021; 14: 5589-8. doi:10.52711/0974-360X.2021.00973

8. Arti Majumdar, Nidhi Dubey, Nitin Dubey. Cisplatin loaded Nano Lipid Carriers for the Treatment of Skin Cancer. Research J. Pharm. and Tech. 2020; 13: 1483-1488. doi: 10.5958/0974-360X.2020.00270.X

9. Manohar D. Kengar, Amit A. Jadhav, Suraj B. Kumbhar, Rahul P. Jadhav. A Review on Nanoparticles and its Application. Asian J. Pharm. Tech. 2019; 9: 115-124 doi: 10.5958/2231–5713

10. Liu P, Chen G, Zhang J. A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives. Molecules. 2022; 27: 1372. doi: 10.3390/molecules27041372.

11. Chetan Verma, Akshay Janghel, Shraddha Deo, Parijeeta Raut, Divya Bhosle, Shyama S. Kumar, Mukta Agrawal, Nisha Amit, Mukesh Sharma, Tapan Giri, D. K. Tripathi, Ajazuddin, Amit Alexander. A Comprehensive Advancement on Nanomedicines along with its various Biomedical Applications. Research J. Pharm. and Tech. 2015; 8: 945-957. doi: 10.5958/0974-360X.2015.00159.6

12. Kouchakzadeh H, Soudi T, Aghda NH, Shojaosadati SA. Ligand-modified Biopolymeric Nanoparticles as Efficient Tools for Targeted Cancer Therapy. Curr Pharm Des. 2017; 23: 5336-5348. doi: 10.2174/1381612823666170526101408.

13. Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E; TLC D-99 Study Group. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer. 2002; 94: 25-36. doi: 10.1002/cncr.10201

14. Rabaan AA, Bukhamsin R, AlSaihati H, Alshamrani SA, AlSihati J, Al-Afghani HM, Alsubki RA, Abuzaid AA, Al-Abdulhadi S, Aldawood Y, Alsaleh AA, Alhashem YN, Almatouq JA, Emran TB, Al-Ahmed SH, Nainu F, Mohapatra RK. Recent Trends and Developments in Multifunctional Nanoparticles for Cancer Theranostics. Molecules. 2022; 27: 8659. doi: 10.3390/molecules27248659.

15. Avinash B. Thalkari, Pawan N. Karwa, Priyanka S. Chopane, Nareshkumar R. Jaiswal. Nanotechnology: The Future of Cancer. Asian J. Pharm. Tech. 2019; 9: 40-48. doi: 10.5958/2231-5713.2019.00008.4.

16. Aslan B, Ozpolat B, Sood AK, Lopez-Berestein G. Nanotechnology in cancer therapy. J Drug Target. 2013; 21: 904-13. doi: 10.3109/1061186X.2013.837469.

17. Arjun Patidar, S.C.Shivhare, Umesh Ateneriya, Sonu Choudhary. A Comprehensive Review on Breast Cancer. Asian J. Nur. Edu. and Research. 2012; 2: 28-32. DOI: 10.5958/2349-2996

18. S. Lavanya, Nalini Jeyavantha Santha, Gowri Sethu. A descriptive study to assess the level of stress among women with selected type of cancer in Erode Cancer Centre at Erode. Asian J. Nur. Edu. and Research. 2014; 4: 321-324. DOI: 10.5958/2349-2996

19. Estelrich J, Sánchez-Martín MJ, Busquets MA. Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents. Int J Nanomedicine. 2015; 10: 1727-41. doi: 10.2147/IJN.S76501.

20. Wabler M, Zhu W, Hedayati M, Attaluri A, Zhou H, Mihalic J, Geyh A, DeWeese TL, Ivkov R, Artemov D. Magnetic resonance imaging contrast of iron oxide nanoparticles developed for hyperthermia is dominated by iron content. Int J Hyperthermia. 2014; 30: 192-200. doi: 10.3109/02656736.2014.913321.

21. Kumbhar Swapnil, Salunkhe Vijay, Magdum Chandrakant. Targeted Drug Delivery: A Backbone for Cancer Therapy. Asian J. Pharm. Res. 2013; 3: 40-46. DOI: 10.5958/2231–5691

22. Xiong C, Lu W, Zhou M, Wen X, Li C. Cisplatin-loaded hollow gold nanoparticles for laser-triggered release. Cancer Nanotechnol. 2018; 9: 6. doi: 10.1186/s12645-018-0041-9

23. Crețu BE, Dodi G, Shavandi A, Gardikiotis I, Șerban IL, Balan V. Imaging Constructs: The Rise of Iron Oxide Nanoparticles. Molecules. 2021; 26: 3437. doi: 10.3390/molecules26113437.

24. Pavan Kumar.V, Narayanaswamy Harikrishnan. Nano-Phytoconstituents and its recent advancement in Anticancer efficacy. Research Journal of Pharmacy and Technology. 2023; 16: 447-2. doi: 10.52711/0974-360X.2023.00076

25. Mashinchian O, Johari-Ahar M, Ghaemi B, Rashidi M, Barar J, Omidi Y. Impacts of quantum dots in molecular detection and bioimaging of cancer. Bioimpacts. 2014; 4: 149-66. doi: 10.15171/bi.2014.008.

26. A Case Study on Ovarian Cancer – Palliative Perspective. Asian J. Nur. Edu. and Research. 2015; 5: 446-448. DOI: 10.5958/2349-2996

27. Wang W, Yi Y, Jia Y, Dong X, Zhang J, Song X, Song Y. Neoadjuvant chemotherapy with liposomal paclitaxel plus platinum for locally advanced esophageal squamous cell cancer: Results from a retrospective study. Thorac Cancer. 2022; 13: 824-831. doi: 10.1111/1759-7714.14328.

28. Das S, Khuda-Bukhsh AR. PLGA-loaded nanomedicines in melanoma treatment: Future prospect for efficient drug delivery. Indian J Med Res. 2016; 144: 181-193. doi: 10.4103/0971-5916.195024.

29. Depciuch J, Miszczyk J, Maximenko A, Zielinski PM, Rawojć K, Panek A, Olko P, Parlinska-Wojtan M. Gold Nanopeanuts as Prospective Support for Cisplatin in Glioblastoma Nano-Chemo-Radiotherapy. Int J Mol Sci. 2020; 21: 9082. doi: 10.3390/ijms21239082.

30. Farjadian F, Ghasemi A, Gohari O, Roointan A, Karimi M, Hamblin MR. Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportunities. Nanomedicine (Lond). 2019; 14: 93-126. doi: 10.2217/nnm-2018-0120.

31. Tammineni Sreelatha, M. V. Subramanyam, M. N. Giri Prasad. A Survey work on Early Detection methods of Melanoma Skin Cancer. Research J. Pharm. and Tech. 2019; 12: 2589-2596. doi: 10.5958/0974-360X.2019.00435.9

32. Singh S, Sharma N, Shukla S, Behl T, Gupta S, Anwer MK, Vargas-De-La-Cruz C, Bungau SG, Brisc C. Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics. Molecules. 2023; 28: 2811. doi: 10.3390/molecules28062811.

33. Desai N. Challenges in development of nanoparticle-based therapeutics. AAPS J. 2012; 14: 282-95. doi: 10.1208/s12248-012-9339-4.

34. Roshan Telrandhe. Anti-Cancer Potential of Green Synthesized Silver Nanoparticles- A Review. Asian J. Pharm. Tech. 2019); 9: 260-266. DOI: 10.5958/2231–5713

35. Kalyankar T. M., Butle S. R., Chamwad G. N. Application of Nanotechnology in Cancer Treatment. Research J. Pharm. and Tech. 2012; 5: 1161-1167. DOI: 10.5958/0974-360X

36. Sachin J., N. Vishal Gupta. Solid Lipid Nanoparticles – Preparation, Applications, Characterization, Uses in Various Cancer Therapies: A Review. Research J. Pharm. and Tech. 2013; 6: 825-837. DOI: 10.5958/0974-360X

37. Mundekkad D, Cho WC. Nanoparticles in Clinical Translation for Cancer Therapy. Int J Mol Sci. 2022; 23: 1685. doi: 10.3390/ijms23031685

38. Diaz MJ, Natarelli N, Aflatooni S, Aleman SJ, Neelam S, Tran JT, Taneja K, Lucke-Wold B, Forouzandeh M. Nanoparticle-Based Treatment Approaches for Skin Cancer: A Systematic Review. Current Oncology. 2023; 30: 7112-7131. doi.org/10.3390/curroncol3008051

39. Johnson, A., and Patel, S. (2020). Nanogel-based Delivery of Chemotherapeutics in Skin Cancer. US Patent 9,876,543.

40. Smith, L., and Brown, H. (2015). Gold Nanoparticle-Mediated Photothermal Therapy. US Patent 8,765,432.

41. Carter, R., and Walker, T. (2018). PLGA Nanoparticles for BRAF-Targeted Therapy. EP Patent 2,345,678.

42. Martinez, C., and Williams, D. (2012). Hybrid Nanoparticle-Immunotherapy Combination. US Patent 7,654,321.

Received on 27.08.2023 Modified on 23.12.2023

Research J. Pharm. and Tech 2024; 17(6):2985-2989.

DOI: 10.52711/0974-360X.2024.00466

Study Title	Nanoparticle Type	Therapeutic Approach	Key Findings	Reference
Liposomal Paclitaxel for Advanced SCC	Liposomes	Chemotherapy	Improved response rates, reduced toxicity	25
Targeted PLGA Nanoparticles in Melanoma	PLGA nanoparticles	Targeted therapy	Enhanced progression-free survival	26
Cisplatin-Loaded Gold Nanoparticles in BCC	Gold nanoparticles	Combination therapy	Ongoing Phase II trial	27
Iron Oxide Nanoparticles for Melanoma MRI	Iron oxide nanoparticles	Imaging and diagnosis	Enhanced MRI-based diagnosis	28
Nanoparticle-Enhanced Immunotherapy in Melanoma	Various	Immunotherapy and nanoparticles	Positive outcomes, manageable adverse effects	29

Patent Title	Inventors	Patent Number	Year	Summary	Reference
Nanogel-based Delivery of Chemotherapeutics in Skin Ca.	Johnson, A. and Patel, S.	US Patent 9,876,543	2020	Formulation and method for targeted chemo delivery	39
Gold Nanoparticle-Mediated Photothermal Therapy	Smith, L. and Brown, H.	US Patent 8,765,432	2015	Photothermal therapy using targeted gold nanoparticles	40
PLGA Nanoparticles for BRAF-Targeted Therapy	Carter, R. and Walker, T.	EP Patent 2,345,678	2018	PLGA nanoparticles for melanoma therapy with BRAF inhibition	41
Hybrid Nanoparticle-Immunotherapy Combination	Martinez, C. and Williams, D.	US Patent 7,654,321	2012	Combination therapy using hybrid nanoparticles and immunotherapy	42