Engineering Nanomedicines for Improved Melanoma Therapy: Progress and Promises

Di Bei; Jianing Meng; Bi-Botti C Youan

Disclosures

Nanomedicine. 2010;5(9):1385-1399. 

In This Article

Abstract and Introduction

Abstract

Once metastatic, melanoma remains one of the most aggressive and morbid malignancies. Moreover, in past decades, the overall survival for advanced unresectable melanoma exhibited a constancy of poor prognosis. Low response rates and serious adverse effects have been characteristic of standard therapy based on a combination of chemotherapeutic agents or immunotherapy with IL-2. For example, the chemotherapy including dacarbazine, carmustin, cisplatin and tamoxifen is known as 'Dartmouth regimen' while the CVD regimen comprises carmustine, vinblastine and dacarbazine. Thus, there is an urgent and critical need to reformulate these bioactive agents using nanoscience and nanotechnology as alternative strategies. This article overviews current design and evaluation of nanomedicine undertaken to address this unmet medical need. The nanomedicines studied include polymeric nanoparticles, liposomes, polymersomes, dendrimers, cubosomes, niosomes and nanodiamonds. In this preclinical article, nanotechnology provides hope for effective treatment of this aggressive and largely treatment-resistant disease.

Introduction

Melanoma (Figure 1), a malignant tumor that claims the majority of deaths in human skin cancer, is one of the most common cancers in adults. Each year, more than 60,000 people in the USA learn that they have melanoma.[1] Approximately 132,000 cases of malignant melanoma (the most fatal kind of skin cancer) and over 2 million cases of other skin cancers occur worldwide each year. One in every three cancers diagnosed worldwide is a skin cancer.[2] Melanoma is rising at a rate faster than that of all preventable cancers, except lung cancer, in the USA.[3]

Figure 1.

Melanoma-containing human skin and possible mechanism of nanoparticle transport by paracellular, transfollicular and intracellular routes (left to right).

If melanoma is found and treated in its early stages, the chances of recovery are very good. If it is not found early, melanoma can grow deeper into the skin and spread or undergo metastasis to other parts of the body. Once it has evolved to malignant melanoma, it is difficult to cure and results in a high death rate.

The current clinical approach and therapy for cutaneous melanoma includes surgery, chemotherapy or immunotherapy, and/or the combination of the two. Surgery remains the best intervention for patients with early-stage melanoma. Many surgeons consider 0.5 cm as the standard for excision,[4] but a 0.2 cm margin might be acceptable for margin-controlled surgery. Tumor recurrence or relapse is a common failure in treatment. Mohs micrographic surgery (also known as chemosurgery[5]) has a cure rate between 97 and 99.8%.[6] Unfortunately, attempts to improve survival by surgically removing lymph nodes result in no overall survival benefits.[7] Other than surgery, there are two major alternatives to this disease management: chemotherapy and immunotherapy. Chemotherapy typically includes administration of dacarbazine, cisplatin, temozolomide and paclitaxel. Dacarbazine is administered alone or in combination with other drugs, including carmustine and cisplatin.[8,9] The combination of dacarbazine, carmustine, cisplatin and tamoxifen is termed the 'Dartmouth regimen'.[8] The combination of cisplatin, vinblastine and dacarbazine is another treatment for melanoma known as the 'CVD regimen'.

The continuous search for better patient outcome had led to immunological approaches to the treatment of malignant melanoma. Multiple peptide, dendritic cell, adjuvant, lymphocyte and virus-based strategies have been established and tested. They reveal some degree of success in preclinical and clinical studies. A recent study in melanoma immunotherapy has demonstrated that complex vaccines and the combination of different approaches, including dendritic cell vaccines in conjunction with costimulatory molecules, are superior to conventional immunization protocols in induction of tumor-specific immune responses.[4]

Although the current therapies have their advantages, they are either not effective enough or they cause serious side effects and toxicity. The two biotechnology-derived drugs that appear most active against melanoma are IFN-α and IL-2. The response rates for INF range from 8 to 22%, and long-term administration on a daily or a three-times-per-week basis appears superior to once per week or more intermittent schedules.[10] The response to IL-2 regimens is similar and is in the range of 10 to 20%.[11–13] In the randomized experiments to date, it has been reported that no drug or combination of therapies is superior to dacarbazine.[8] Therefore, an urgent need exists to produce novel drug delivery systems, perhaps using nanoscience and nanotechnology, which offer improved efficacy and fewer side effects, particularly in melanoma therapy.[14–17]

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