PLGA-Alendronate Conjugate as a New Biomaterial to Produce Osteotropic Drug Nanocarriers

Abstract

Targeting bone tissue to treat specific diseases, such as primary tumour or bone metastases from peripheral malignancies is a current and pressing research field for modern pharmaceutical technology, and nanomedicine in particular. Bone is the third most common site of metastasis and the incidence of bone metastases in patients died of cancer is reported to be around 70% [1,2]. Primary carcinomas of the lung, breast, prostate, kidney, and thyroid may develop skeletal metastases. In children affected by disseminated neuroblastoma bone metastases are also highly frequent. Tumour osteolysis is responsible for pathologic fractures, intractable pain, nerve compression syndrome, and severe hypercalcemia. In addition, patients with bone metastases may have neurologic impairment from spinal lesions, anaemia, and complications exacerbated by immobilization. Bone matrix resorption is minimally due to direct cancer cell activity. In fact, bone-colonizing tumour cells also stimulate osteoclastmediated bone resorption via the secretion of potent osteolytic agents [3]. The increased bone resorption that follows releases bone-derived growth factors into the extracellular milieu and systemic circulation, thereby further enhancing bone resorption, promoting tumour growth, and altering the tumour microenvironment. Vice versa, metastatic cancer cells are largely influenced by messages embedded within the bone matrix [4]. Under the influence of bone microenvironment, tumour cells proliferate and interact with osteoblasts and osteoclasts leading to lytic or sclerotic lesions. Clinical management of metastatic bone disease is really hard. The probability of long-term survival decreases dramatically in patients with skeletal metastases. Current treatments are based both on systemic therapy (chemotherapy, immunotherapy, hormone therapy) [5,6] and local therapy (surgery and radiotherapy) [7,8]. The restoration of functionality and mobility, along with pain relief can improve patients’ quality of life, but is unable to affect the negative progression of the disease. Because of the unique characteristics of tumours growth within bone tissues, conventional therapeutic strategies often lack efficiency in cure bone metastases. Moreover, most of the drugs used for the adjuvant therapy of osteolytic metastases interfere with signalling that induce osteoclast differentiation and osteoclast-mediated bone resorption, but they are not effective on tumour growth in the bone and their use is obviously associated with heavy side effects.