*1.1. Why Nanoparticles?*

There are many di fferent types of NPs that have promising biomedical applications, e.g., polymeric NPs, polyethylene glycol (PEG)-ylation modified particles, micelles, liposomes, dendrimers, and nanosized inorganic materials [1]. Organic NPs vary in their activity in di fferent biological systems including penetration depths in tissues and their toxicity and targeting e fficiency [2]. Inorganic NPs regularly display novel physical properties as their size is close to nanometer scale measurements. For instance, the extraordinary physical and chemical properties of these NPs may prompt future applications in drug delivery and biomedical imaging. Plenty of sophisticated and di fferent applications, including diagnosis and therapy and flow investigation, are related to configuration of the high surface-to-volume proportions of NPs as a potential system for these strategies. Structures such as core/shell NPs can show improved properties and increased usefulness due to their changed chemical distinction and nanostructured parts. This article therefore features an assortment of structures and properties that can be acknowledged in materials dependent on inorganic NPs and focuses on discussing major inquiries brought up in controlling these properties.

Typical characteristics of inorganic nanomaterials, such as ease of fabrication, modification and functionalization, simple preparation methods, resistance to microbial attacks, high stability and suitable size for cells (plasma membrane below 100 nm), a low toxicity profile, biocompatibility, and having a hydrophilic nature, make them suitable as drug carriers [3]. Moreover, these NPs can be biodegradable, non-toxic, non-immunogenic responsive, have a high loading capacity, and have the capacity for controlled drug release. These characteristics are desired for biomedical applications in addition to properties such as magnetism. However, in practice, it is not easy to fabricate ideal NPs which have all the desired properties [4,5] and some NPs are indeed not suitable for biomedical applications. To improve their biocompatibility, protective coatings which can be non-toxic, such as natural polymers (carbohydratesand peptides) or synthetic polymers (e.g., PEG, polyvinyl alcohol (PVA), and polyglycolic acid (PGA), etc.) can be used. Figure 1 shows a cut-out model of an inorganic NP functionalized with biomolecules for biomedical applications [6].

**Figure 1.** A model design of an inorganic nanoparticle (NP) functionalized with biomolecules for biomedical applications [6]. Reproduced with copyright permission from Springer Nature, 2010.

### *1.2. Why a Nanoporous Membrane?*

Membranes have several biological functions which are useful in sensing, sorting, imaging, separating, and releasing bioactive/drug molecules. Engineered nanoporous and microporous membranes have been developed for their usage in drug delivery. The latest advancement in technology is therefore possible for use in regulating the physico-chemical properties of membrane pores, which make them attractive for controlling drug delivery rates. In addition, di fferent types of materials are used for the fabrication of membranes and their properties and surface modification in order to improve the functions of the membranes, providing di fferent invitro and in vivo applications of therapeutic delivery. In spite of the extensive work carried out for preparation, characterization, and biological evaluation of membranes, there are still a number of challenges which need to be overcome to develop biological membranes.

Membranes are used to control the rate of delivery of drugs to the body as well as drug permeation from the reservoir to attain the required rate of drug delivery. Therefore, drug delivery is controlled by both passive di ffusion and biodegradation mechanisms. Membranes can carry one or more bioactive agents and have been developed into di fferent classes of carriers. These di fferent carriers can be carbon-based nanomaterials, polymeric membranes, and inorganic membranes, where the bulk properties of the membrane are governed by its building blocks, i.e., the NPs. Keeping this in mind, the current review aims to highlight the role of both pharmaceutical NPs and membranes during the last fifteen years based on their preparation method, size, shape, surface functionalization, and drug delivery potential. The following classification gives an overview structure of the article (Figure 2).

**Figure 2.** Structural overview of the article.

### **2. Drug Delivery System**

Since the emergence of controlled drug delivery systems (DDS) in early the 1970s, these systems have attracted increasing attention. DDS are aimed at delivering drugs using pre-defined doses and drug delivery rates. Moreover, the area of drug delivery is an expanding domain focused on targeting genes or drug formulations to a group of diseased cells or tissues. The objective of this technique is to carry an appropriate amount of drug to the target sites (such as diseased tissues and tumors, etc.) while limiting undesirable reactions of the drugs within healthy tissues [7]. The propensity of the carrier material to cure cancer has been influenced by various parameters that relate to the carrier material, e.g., the immune response to the carrier material and uncontrollable drug behavior [8]. The morphology of NPs also performs a significant role in drug loading and release and achieving the maximum cell viability and minimum cell morbidity [9]. In order to illustrate how NPs have been used as DDS, we provide a number of key examples below.

### *2.1. Calcium Phosphate NPs*

Calcium phosphate (CaP) is a common NP used in biological systems and medical applications, especially within those related to diagnosis and treatment. In particular, CaP NPs are extensively used in imaging, bone/tooth repair, and DNA delivery in cell biology [10,11]. The widespread uses of CaP NPs are due to their presence as a natural component in the body, as CaP is well enhanced and easily absorbed in the circulatory system [12]. Hence, previous studies have shown that CaP NPs can be used as a drug carrier. Kester et al. [13] have assessed the ability of CaP NPs to be encapsulating hydrophobic antineoplastic chemotherapeutics. Furthermore, these NPs have shown their ability to encapsulate both fluorophores and chemotherapeutics. These NPs have a diameter of 20–30 nm and pH sensitivity, as well as little degree of disparity. In addition, these NPs have been observed to be steady in physiological solution for a time duration at a surrounding temperature of 37◦C. Bastakoti et al. [14] have claimed that colloidal NPs smaller than 100 nm filled with fluorescent pigments and anticancer drugs have resulted in the successful enhancement of robust biocompatible nanocomposites carriers for simultaneous release of drug molecules and imaging agents.

Shinto et al. [15] have utilized hydroxyapatite porous ceramic blocks (a CaP-based material) NPs in order to formulate nanocarriers for sustained delivery of antibiotics. Firstly, the cylindrical cavities in the hydroxyapatite blocks were loaded with the antibiotic and they were further implanted in the bone defect sites. The results revealed that a higher concentration of the antibiotic was released after seven days of implant. Then, there was a gradual decrease in the concentration after 12 weeks. Overall, the release of antibiotics with an e fficiency of 70% was obtained.

Zhao et al. [16] have investigated the drug delivery ability of anticancer drug docetaxel-loaded lipid-calcium phosphate hybrid NPs, where the NPs showed a high drug loading capacity and biocompatibility. The NPs used in this study had a diameter of 72 nm. Mukesh et al. [17] have also proposed the use of CaP NPs as a carrier for the anticancer drug methotrexate; the size of the NPs in their case was 262 nm, with an encapsulation e fficiency of 58%.They showed a low release rate of methotrexate at physiological pH and the authors observed that over 90% release was obtained in 3 to 4 h at endosomal pH. Liang et al. [18] have examined the in vitro delivery of the anticancer drug doxorubicin (DOX) hydrochloride from CaP hybrid NPs with particle sizes smaller than 50nm. Heparin/CaCO3/CaP NPs were loaded with this anticancer drug. It was observed that the unloaded hybrid NPs showed high biocompatibility while the anticancer loaded NPs exhibited a strong cell inhibitory e ffect. These examples sugges<sup>t</sup> a clear potential for CaP NP use in biomedical applications. CaP NPs have demonstrated successful delivery of drugs and bioactive molecules alone or in combination with polymers, owing to their biocompatibility. However, more research e fforts should be focused in the future on investigating CaP NP degradation products in vivo and their e ffects on the vital organs.

### 2.1.1. Magnetic Mesoporous CaP NPs

Magnetic mesoporous CaP NPs with high water solubility and a diameter of 41 nm have been fabricated by Rout et al. [19]. These CaP NPs were composed of platinum pharmacophorecis-diaquadiamine platinum, folic acid, and rhodamine isothiocyanate, in order to use them against human cervical carcinoma cells. It was observed that the targeting of these cancer cells and delivery of cisplatin could be achieved by utilizing magnetic CaP NPs, as confirmed by cell apoptosis that was followed by cell death. However, no information was reported about their clearance from the body on both bases of animal models and clinical trials.

### 2.1.2. Porous Silica CaP NPs

El-Ghannam et al. [8] have used porous silica CaP NP as a carrier for 5-fluorouracil, which is considered very cytotoxic for 4T1 mammary tumor cells. The invitro study demonstrated that the NPs loaded with the anticancer drug possessed characteristics of burst release (the maximum

release rate) in the first 24 h, and, following this, a sustained release, which was observed for the next 32 days. Meihuaet al. [20] have reported the preparation of mesoporous silica NPs coated with a CaP-hyaluronic acid hybrid. The core shell was further coated with another hyaluronic acid layer in order to target CD44 over-expressed cancer cells. The authors proved that the anticancer release in an acidic subcellular environment could be controlled using their NPs. These studies exhibited the superiority of core shell nano-systems over normal nanomaterials in the delivering of anticancer in a sustained manner.

## *2.2. Carbon-Based Nanomaterials*

Other types of nanomaterials that may be utilized in therapeutic delivery, and especially for anticancer therapy, are carbon-based nanomaterials, including carbon nanotubes (CNTs), graphene oxides (GOs), and nano-diamonds (NDs), as discussed below.

## 2.2.1. Carbon Nanotubes

When carbon atom nanostructures are arranged in a tube-like hollow cylindrical shape, they may be called carbon nanotubes (CNTs) [21]. These are divided into three categories: single-walled carbon nanotubes (SWNTs), double-walled carbon nanotubes (DWNTs), and multi-walled carbon nanotubes (MWNTs). Their diameters may range between several angstroms and tens of nanometers while their lengths may reach half a meter [22,23].

One of the biggest benefits of carbon nanomaterials in biomedical applications is their ability to be a drug carrier. Pastorin et al. [24] have reported that, as an anticancer drug, methotrexate linked via a covalent bond to carbon nanotubes with fluorescein isothiocyante (FITC) was more effectively internalized through folate receptors into cells in comparison to the free drug. CNTs have also been designed to be tumor targetable through functionalization to be used as drug carriers. Moreover, SWNTs have also been used as drug carriers in their water-soluble PEG-ylated form. They have demonstrated a loading capacity for the anticancer drug DOX [25]. MWNTs have been examined as a drug carrier, and in particular oxidized MWNTs have been PEG-ylated for anticancer drug specific delivery to the brain for the treatment of glioma. Other polymers have also been utilized as functionalizing agents for CNTs for drug delivery applications, as has been reported previously [26]. MWNTs have been functionalized with a polyethylenimine (PEI) composite, which has shown impressive biocompatibility. Furthermore, these composites were designed to be accompanied by FITC and prostate stem cell antigen (PSCA) monoclonal antibody (mAb). Finally, a CNT-PEI (FITC)-mAb composite has been obtained which showed impressive biocompatibility with a cancer-cell-targeted delivery system [27].

Cellular uptake of CNTs has been explained by Bhatt et al. [28]. They have suggested mechanisms for CNT cell-internalization via two pathways, namely, dependent and independent endocytosis pathways, where the endocytosis-independent pathway is divided into two types: receptor-mediated endocytosis and non-receptor-mediatedendocytosis (see Figure 3). CNTs with their available types either functionalized or not have demonstrated grea<sup>t</sup> success in the delivery of bioactive molecules, especially anticancer agents, and the targeting of tumor cells.This has encouraged scientists to explore their applicability within most common diseases other than cancer. Nevertheless, CNTs have not been explored widely, owing to their difficult and expensive preparation methods.

**Figure 3.** Receptor-mediated endocytosis of CNTs. (**1**) Association of ligand conjugated drug-loaded CNTs with receptor; (**2**) endosomal internalization of conjugates, (**3**) drug release, and (**4**,**5**) receptor regeneration [28]. Reproduced with copyright permission from Elsevier, 2016.
