Potential applications of multifunctional mesoporous carbon nanoplatform for tumor microenvironment improving by combined chemo-/phototherapy

Abstract

At present, conventional drug therapy for tumor strongly stimulates tumor tissue, leading to tumor necrosis and acute inflammatory response, and tumor metastasis. How to kill tumor cells under mild conditions and prolong the survival of patients is a hot topic of tumor therapy. In this study, a multifunctional nanoplatform was designed based on mesoporous carbon nanoparticles, grafting with anti-inflammatory drug (celecoxib) and loading chemotherapy drug (doxorubicin). The constructed nanoplatform mesoporous carbon/celecoxib @doxorubicin was found to capable of, induce intravascular thrombosis, blocking nutrient supply for tumor, and over-inflammatory suppression avoiding acute tissue necrosis. Meanwhile, this study demonstrates combined chemo- and photothermal therapy and exhibits a promising potential in cancer therapy.

Introduction

Photothermal therapy has becoming one of the most extensively studied modality for tumor ablation by quickly killing the tumor cells, however, the over-high temperature tumor ablation may cause significant damages to the surrounding normal tissues, meanwhile the mild hyperthermia may trigger neovascular that is beneficial to inflammation [1] and metastasis.

Firstly, inflammation is a response of body tissues to endogenous/exogenous injuries, which plays an important part in potent immune and repair response. When exogenous invasion of the body, the defense system is mobilized to fight, then chemokines and inflammatory factors recruit and activate immune cells to eliminate exogenous invasion. However, this intense struggle will inevitably cause local damage. In tumor, the damage could prevent further treatment [2]. Over-inflammatory environment [3] can lead to tissue necrosis [4], tumor growth, invasion [5], metastatic dissemination [6] under certain circumstances [7]. It is recognized that chronic inflammation [8,9] play a key role in colorectal cancer (CRC) and has been demonstrated to promote cancer development [10,11]. This suggests that anti-inflammatory agents may be used to control the development and progression of tumors [12] and inhibit expression of proinflammatory cytokines, tumor growth factors, activates nuclear factor kappa B(NF-κB). Meanwhile, NF-κB is an important regulator, which activates tumor escape by promoting the expression of related genes and adhesion protein.

Recent researches have showed that non-steroidal anti-inflammatory drugs [13] (NSAIDs) rofecoxib or celecoxib selectively could inhibit cyclooxygenase-2 (COX-2) for preventing of cancers in clinic [14]. Overexpressed COX-2 [15] induces synthesis of prostaglandins (PGs) [16], which activates PGs receptors and inhibits tumor cell apoptosis, enhance tumor proliferation, promoting angiogenesis, improving the invasion and migration of tumors, and inhibit immune responses [17,18]. However, The COX-2 in endothelial cells catalyzes the production of PG2I, which is inhibited by celecoxib, resulting in the imbalance of PG2I/TXA2, which leads to serious vascular thrombosis. More and more evidences show that blood vessels that supply nutrients, play a crucial role in tumor sustainability. The vascular thrombosis eventually caused the tumor to starve to death.

Carbon materials are susceptible to surface functionalization, which enable them to be used as multifunctional drug-carried system [19]. To date, chemically inactive and highly biocompatible mesoporous carbon nanoparticles (MCNs)-based [20,21] drug carrier system has attracted extensive attention [22,23] due to their ordered porous structure [24], controllable pore size, larger specific surface area and easy surface modification [25,26]. These drugs are entrapped in pore channels of MCN [27]. Furthermore, MCNs showed high photo-thermal conversion efficiency in the near-infrared (NIR) (wavelength 700–1100 nm) region [28]. Photothermal therapy [29], a physical treatment modality, converts light into heat to kill tumor cells. Upon entering into cancer cell, the temperature would be elevated increase from MCN upon near-infrared irradiation for potential photothermal therapy(PTT). However, the excess inflammation, induced by thermal-chemotherapy, cause damage to normal tissue and seriously hinder the treatment process, and is the important reason for poor prognosis. This nanoplatform [30] not only has an outstanding enhanced efficacy for inhibition cancer cells preventing damage of healthy tissues, but also enables synergetic photothermal therapy (PTT) and chemotherapy [31]. Meanwhile combination therapy [32,33] is currently the most commonly used treatment for cancer [29].

In this paper, the ultimate goal is to design a multifunctional nanoplatform to improve therapeutic effect and reduce the risk of tumor metastasis [34].A nonsteroidal anti-inflammatory drugs, celecoxib (CEL) and anti-cancer drug, doxorubicin(DOX), were respectively grafted onto and loaded into the mesoporous carbon carrier. This research demonstrates that the multifunctional nanoplatform has good bio-safety in vivo, and provides a feasible strategy to restrain excessive inflammatory responses and block tumor blood vessels. Moreover, this nanoplatform demonstrates promising potentials in blocking nutrient supply [35], inhibiting the growth of tumors and preventing cancer cell metastasis.