Passive Targeting And The Epr Effect

Although active targeting may be achieved through targeting to folate receptors, angiogenesis, or targets more specific to the cancer being treated, some enhancement of treatment to cancers on account of the EPR effect cannot be ignored and should be utilized until more specific targeting systems can be developed. Preparation of nanoparticle systems that can avoid uptake by the reticuloendothelial system (RES) is essential, and such particles are often referred to as "stealth" nanoparticles.

The most effective polymer used as a coating on nanoparticles to avoid detection by the RES is poly(ethylene glycol).13 The latter can be achieved by adsorption of the PEG-containing polymer onto the surface of nanoparticles, direct conjugation of the PEG to the nanoparticles, or inclusion of PEG in the polymeric backbone that makes up the nanoparticles. The PEG itself may then also be modified to give targeting capabilities and to avoid uptake by the RES. The PEG works to mask the surface of the nanoparticles by reducing the plasma and protein adsorption to the particles, reducing the complement activation and hence the recognition of the PEG as a foreign substance in the blood stream. The longer circulation time afforded PEGylated nanoparticles allows them time to be targeted, whether passively or actively, to cancerous tissues.

Extended circulation time and enhanced tumor targeting were seen for poly(ethylene oxide)-modified poly(epsilon-caprolactone) nanoparticles in mice with tumors of MDA-MB-231, a human breast carcinoma.14 These particles were loaded with [3H]-tamoxifen. The amount of labeled tamoxifen at the tumor site, 6 h after injection, for those particles with PEO modification was at least twice that of particles without modification and four times that of labeled tamoxifen injection. The amount of labeled tamoxifen found in the blood stream at 6 h after injection was also at least twice that of the injection or unmodified nanoparticle formulations.

The stability and circulation of PLGA-mPEG nanoparticles containing cisplatin was investigated. It was found that while the mPEG content affected the drug release rate, the drug loading level had no effect on the drug release rate for in vitro studies.15 The release was more that 60% completed within the first 12 h in all cases. Data for blood levels was only presented for 3 h, so it is hard to draw any valid conclusions from this information.

Nanoparticles of PLA and PEG-PPG-PEG were prepared containing irinotecan, a prodrug of an analogue of camptothecin.16 Although little characterization beyond the average particles size (231 nm) was presented here and no in vitro studies were described, the in vivo studies are quite interesting. In this study, there was a modest increase in survival time in mice with M5076 tumors (early liver metastatic stage) after a single injection and more pronounced increases in survival time after either two or three repeat injections. It is noteworthy that the greatest survival times (20% survival at 45 days at the end of the study) were seen with two injections at days three and five after the implantation of the tumor.

Polycyanoacrylate nanoparticles have long been studied by Couvreur and collaborators as biodegradable nanoparticles for a variety of applications and therapies which are not limited to treatment of cancer.17 A recent work describes the effectiveness of these nanoparticles as delivery systems for brain tumor targeting. Here they studied uncoated and PEG-coated nanoparticles and found that both types of particles showed accumulation in a well-established 9L gliosarcoma in rat studies. The PEG-coated particles showed the highest accumulation, with a tumor-to-brain ratio of 11.

Poly(butyl cyanoacrylate) nanoparticles containing doxorubicin were prepared with no surface modifications; the in vivo distribution of 99mTc labeled nanoparticles was evaluated in mice inoculated with Dalton's lymphoma tumor cells.18 The nanoparticles were administered by subcutaneous injection and the concentration in a number of organs was followed for 48 hours and compared with that for 99mTc labeled doxorubicin alone. When compared with the amount of doxorubicin alone, the amount of radioactivity in the tumor was higher at all times tested, with a 13-fold increase seen at 48 h.

While the majority of work on targeted nanoparticles has been carried out with polylactides, polyglycolides and polycyanoacrylates, those are not the only materials that can be used in nanoparticles. Some recent work with radiolabeled gelatin nanoparticles modified with poly(ethylene glycol) showed that adding the PEG to the surface of these nanoparticles increased the circulation time in mice with double the amount of PEG-modified nanoparticles in the blood stream 3 h after injection compared to the amount of control nanoparticles.19 In addition, there was a four-fold increase in the amount of PEG-modified gelatin nanoparticles found in the tumor 4 h after injection and later when compared to the number of nonmodified gelatin nanoparticles.

12.4 TARGETING TO ANGIOGENESIS

A recently explored and potentially promising target of cancer drug and gene nanoparticle therapy is tumor angiogenesis. It is now well established that tumor growth is dependent on new capillary infiltration from surrounding, preexisting vasculature.20,21 This is an important control point in cancer as much research has proven that tumors cannot effectively grow past a small size or metastasize without blood supply.22-24 Except for the cases of menstruation, wound healing, and tissue regeneration, capillaries do not increase in size or number under normal physiological conditions. Tumor growth is an exception to this physiological rule.

Tumors are typically unable to affect angiogenesis when they are small and surrounded by healthy tissue. However, at the point in growth where nutrients, oxygen, and growth factors can no longer reach the cancer cells, blood flow is required to allow further growth of the tumor. After what is occasionally a substantial time period, the tumor may abruptly induce angiogenesis into the tissue.23 Because understanding this step in the progression of cancer is thought to be of great importance, much research has been and continues to be focused on pinpointing the progression of cancer and on targeting the event for therapy.

Much research has focused on targeted therapy of either chemotherapeutic agents to sites of tumor angiogenesis or of angiogenesis-inhibiting drugs to tumors with the goal of directly combatting the proliferation of newly forming capillaries in the tumor. Angiogenesis is a complex, multi-component process that involves many cell types, cytokines, growth factors and receptors, proteases, and adhesion molecules.25 As a result, there are many potential targets for anti-angiogenic or chemotherapeutic therapy. Some recent advances in targeting approaches for nanoparticle drug delivery are discussed below.

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