Polymeric Nanoparticles

Sub-micronic particles prepared from polymers are becoming increasingly popular for the delivery of drugs or genes to tumor tissues. When compared to all other colloidal delivery systems, nanoparticles have better stability in plasma and higher encapsulation efficiency, and they are amenable to large-scale preparation. These nanoparticles can be used to increase the solubility of hydrophobic drugs, lower the toxicity of drugs with a high therapeutic index, and enhance the stability of the payload, in the case of DNA, by protecting it from degradation by extracellular enzymes. Furthermore, these particles permit controlled release of the payload at the target site at relatively low doses.19 In addition, there is a wide range of polymeric materials whose physicochemical properties can be tailored to achieve polymeric nanoparticles of the required nature.

Passive targeting of these particles at the tumor sites is generally achieved by the enhanced vascular permeability and lack of lymphatic drainage, together termed the enhanced permeability and retention effect (EPR) (Figure 13.1).12-14 The accumulation of polymeric nanoparticles carrying drugs is dependent on the physical chemistry of the polymer, including molecular weight, surface charge, nature of the polymer, etc. The EPR is one of the main reasons for the success of polymeric nanoparticles in targeting tumors. Site-specific or active targeting of these particles can be achieved by conjugating with targeting moieties or ligands that are specific to the tumor cells. These targeting moieties present on the polymer backbone are used to exploit the differences between tumor cells and normal cells through receptor-mediated endocytosis. Active targeting, in particular, can be used to overcome the obstacle of tumor metastasis and to increase the specificity and efficacy of the polymeric carrier system. Transferrin, folate, epidermal growth factor, and argenine-glycine-aspartic acid (RGD) tripeptide are some of the moieties that are used for targeting tumor cells.7,20-26

The major drawback to the use of nanoparticles in cancer therapy is their initial burst release of the drug upon administration into systemic circulation that is followed by slow controlled release of the encapsulated drug. The polymers used in the preparation of nanoparticles generally lack the ability to encapsulate both hydrophilic and hydrophobic drugs in the same polymer system (i.e., the hydrophilic drugs have to be encapsulated in a hydrophilic polymer). Some of the synthetic polymers have cytotoxicity issues associated with them. However, this difficulty could be overcome by using biosynthetic polymers that are biodegradable and modified to have physicochemical properties similar to those of the synthetic polymers. The use of polymeric nanoparticles for systemic delivery must be limited to non-cationic or surface-modified polymers to prevent adsorption of plasma proteins onto the surface of the nanoparticles. Furthermore, some of the naturally occurring polymers have immunogenic reactions when injected into blood; such reactions could be prevented through the use of non-immunogenic biopolymers now available.

PEG-Modified Polymeric Nanoparticles

Extravascular Space """^-s

Extravascular Space """^-s

Blood Capillary Endothelial Cells

Extravascular Space \ Leaky Vasculature

FIGURE 13.1 Schematic of enhanced permeability and retention effect. Passive targeting to the tumor cells is achieved by the extravasation of the polymeric nanoparticles through the leaky vasculature of the blood capillaries in the tumor. The leaky vasculature, along with the lack of lymphatic drainage, is called the EPR effect and is used to passively target nanocarriers to the tumor.

Blood Capillary Endothelial Cells

Extravascular Space \ Leaky Vasculature

FIGURE 13.1 Schematic of enhanced permeability and retention effect. Passive targeting to the tumor cells is achieved by the extravasation of the polymeric nanoparticles through the leaky vasculature of the blood capillaries in the tumor. The leaky vasculature, along with the lack of lymphatic drainage, is called the EPR effect and is used to passively target nanocarriers to the tumor.

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