Controlled Release Microparticles

Different types of anticancer drugs have been incorporated into biodegradable microparticles (62-69). Compared to implants these systems offer the advantage that they can be injected directly into the wall of the resection cavity (the neighboring tissue of the debulked tumor) at multiple positions. As drug transport within the brain tissue is generally restricted to a few millimeters, this type of devices allows to more easily cover larger brain regions. For instance, Emerich et al.(67) compared the efficiency of carboplatin- and BCNU-loaded, PLGA-based microparticles that were injected either into the resection cavity or into the tissue surrounding the resection cavity of tumor bearing rats that underwent surgical removal. The microparticles that were injected into the tissue were administered at four

Plga Microparticles

Figure 10 Effects of the drug loading and co-polymer composition of BCNU-loaded p(CPP:SA)-based wafers on the survival of 9L-gliosarcomas-bearing rats treated 5 days after tumor implantation with discs based on: (A) 20:80 p(CPP:SA); and (B) 50:50 p(CPP:SA). The drug contents are indicated in the figures. Blank wafers (free of drug) were studied for reasons of comparison (n = 8 for each group). Source: From Ref. 55.

Figure 10 Effects of the drug loading and co-polymer composition of BCNU-loaded p(CPP:SA)-based wafers on the survival of 9L-gliosarcomas-bearing rats treated 5 days after tumor implantation with discs based on: (A) 20:80 p(CPP:SA); and (B) 50:50 p(CPP:SA). The drug contents are indicated in the figures. Blank wafers (free of drug) were studied for reasons of comparison (n = 8 for each group). Source: From Ref. 55.

separate sites, approximately 5 mm from the edge of the resection cavity in a diamond-shaped configuration. In addition, control groups that: (1) underwent no resection; (2) underwent resection only; or (3) received a bolus drug injection were studied. The drug amount administered with the microparticles was either 10, 50, or 100 mg/rat, the bolus control drug injection contained 100 mg drug/rat. As an example, Figure 11(A and B) shows the observed survival rates of the respective animal groups treated with carboplatin (please note the different scaling of the x-axes). Clearly, the efficiency of the treatments increased in the following order: no resection <resection only< bolus injection< sustained release microparticles injection (drug amount: 10 mg<50 mg<100 mg). This was true also for BCNU (data not shown). Importantly, carboplatin-loaded microparticles were more effective when injected into the surrounding tissue compared to an administration into the resection cavity (Fig. 11B vs. 11A). This can at least partially be attributed to the fact that carboplatin diffusion into the brain tissue is limited: Atomic absorption spectrophotometry measurements showed that the drug was distributed within an area of approximately 0.5 mm from the implantation site.

Another interesting advantage of controlled release microparticles compared to larger implants is the possibility to inject them directly into inoperable tumors. Using standard needles anticancer drug-loaded systems can be administered by stereotaxy without causing major damage to the brain tissue. For instance, the group of Benoit and Menei developed 5-fluorouracil-loaded, PLGA-based microparticles that can be used for both: the treatment of operable as well as inoperable malignant gliomas (62-66,70). Due to the significant progress in neurosurgery it is nowadays possible to precisely inject small volumes of microparticle suspensions at any position in the brain. Using a stereotaxic frame (or even frameless) computer-assisted neurosurgery (neuronavigation) can guide the implantation of electrodes, catheters, injections or the realization of biopsies (71). The morbidity of stereotaxic procedures is low (<1%). Due to their small size (often <100 mm), anticancer drug-loaded microparticles can be easily administered using these techniques in discrete, precise regions of the brain. For example, Figure 12 shows: (1) the stereotaxic intracranial implantation of microparticles into an anaesthetized rat using a stereotaxic frame; (2) successfully administered microparticles in the striatum of a rat brain; (3) a navigation software neurosurgeons can use to guide their injections; and (4) the stereotaxic implantation of anticancer drug-loaded microparticles into a human brain. Importantly, PLGA-based micro-particles are completely biodegradable and are biocompatible with brain tissue (72,73). Figure 13A and Figure 13B shows optical micrographs of such particles 24 h and 3 weeks after injection into rat striatum, respectively. As it can be seen in Figure 13B, some microparticles were vacuolized.

Formulation Design

Figure 11 Survival of rats upon surgical brain tumor removal and subsequent carboplatin administration into (A) the resection cavity; or (B) the surrounding tissue. The drug was administered either as a bolus injection (drug amount =100 mg/ rat), or in the form of controlled release microparticles (drug amount = 10, 50 or 100 mg/rat, as indicated). In the case of microparticle injection into the surrounding tissue, the total dose was divided into 4 equal parts that were administered at 4 separate sites. "No resection" and "resection only" controls were studied for reasons of comparison. Source: From Ref. 67.

Figure 11 Survival of rats upon surgical brain tumor removal and subsequent carboplatin administration into (A) the resection cavity; or (B) the surrounding tissue. The drug was administered either as a bolus injection (drug amount =100 mg/ rat), or in the form of controlled release microparticles (drug amount = 10, 50 or 100 mg/rat, as indicated). In the case of microparticle injection into the surrounding tissue, the total dose was divided into 4 equal parts that were administered at 4 separate sites. "No resection" and "resection only" controls were studied for reasons of comparison. Source: From Ref. 67.

Figure 12 Stereotaxic administration of biodegradable microparticles into the brain: (A) In an anaesthetized rat using a stereotaxic frame; (B) imaging of microparticles that have successfully been injected into the striatum of a rat brain (indicated by the arrow); (C) programming of a stereotaxic intratumoral administration of microparticles using computer-assisted neurosurgery; (D) stereotaxic administration of 5-fluorouracil-loaded microparticles into a human brain. Source: From Ref. 65.

Figure 12 Stereotaxic administration of biodegradable microparticles into the brain: (A) In an anaesthetized rat using a stereotaxic frame; (B) imaging of microparticles that have successfully been injected into the striatum of a rat brain (indicated by the arrow); (C) programming of a stereotaxic intratumoral administration of microparticles using computer-assisted neurosurgery; (D) stereotaxic administration of 5-fluorouracil-loaded microparticles into a human brain. Source: From Ref. 65.

A phase I clinical trial with 5-fluorouracil-loaded, PLGA-based microparticles for the treatment of operable malignant gliomas was reported in 1999 (63). The principle of this treatment method is illustrated in Figure 14. The tumor (marked as a black circle) is removed by surgical resection; the surrounding infiltrated tissue remains in the brain. To reduce the resulting risk of local tumor recurrence, the anticancer drug-loaded microparticles are injected into the wall of the resection cavity. Eight patients with newly diagnosed glioblastoma were included in this trial, who received in addition external beam radiation. They were followed by clinical examination, magnetic resonance imaging as well as 5-fluorouracil assays in the blood and cerebrospinal fluid (CSF). The anticancer drug was detectable during at least 1 month upon administration in the CSF, whereas the concentrations in the blood were lower and transitory. The systemic

Figure 13 Optical microscopy pictures of PLGA-based microparticles upon implantation into the rat striatum, after (A) 24 hours, and (B) 3 weeks (some micro-particles are vacuolized). Source: From Ref. 72.

tolerance to the treatment was good. Importantly, the median survival time was 98 weeks from the time of implantation and 2 patients achieved complete remission at 139 and 153 weeks, respectively. Based on these encouraging results, a randomized, multicenter phase II clinical trial with these 5-fluorouracil-loaded, PLGA-based microparticles was conducted (64,65). All patients that were included suffered from high-grade gliomas, underwent tumor resection and received external beam radiation. One group of patients also received the anticancer drug-loaded microparticles (130 mg 5-fluorouracil, injected at multiple sites into the surrounding tissue) (Arm A), the other group of patients did not (Arm B). Ninety five patients were randomized, 75 were treated and analyzed in intention to treat for efficacy

Tumor

(B) Surgical resection (C) Microparticle injection

Figure 14 Principle of the treatment of operable brain tumors with 5-fluouracil-loaded, PLGA-based microparticles. Schematic cross-sections through a human brain: (A) The tumor is illustrated as a black circle; the surrounding tissue is infiltrated by tumor cells. (B) The tumor has been removed surgically. (C) To minimize the risk of local tumor recurrence, drug-loaded microparticles are injected into the wall of the resection cavity at multiple locations.

Tumor

(B) Surgical resection (C) Microparticle injection

Figure 14 Principle of the treatment of operable brain tumors with 5-fluouracil-loaded, PLGA-based microparticles. Schematic cross-sections through a human brain: (A) The tumor is illustrated as a black circle; the surrounding tissue is infiltrated by tumor cells. (B) The tumor has been removed surgically. (C) To minimize the risk of local tumor recurrence, drug-loaded microparticles are injected into the wall of the resection cavity at multiple locations.

and safety. The overall survival in Arm A was 15.2 months versus 13.5 months in Arm B. In the subpopulation of patients with complete resection, the overall survival was 15.2 months in Arm A versus 12.3 months in Arm B. Thus, the treatment of the patients with this type of local controlled drug delivery system increased the overall survival. However, the differences were not statistically significant in this study (that was not designed and sufficiently powered to demonstrate this).

A phase I clinical trial with this type of 5-fluorouracil-loaded, PLGA-based microparticles to treat inoperable brain tumors was reported in 2004 (74). Ten patients with newly diagnosed, inoperable malignant gliomas were included. The microparticles (containing 132 mg anticancer drug) were administered by stereotaxy directly into the tumor in one or several trajectories with 1-7 deposits per trajectory. The patients also received external beam radiation and were followed by clinical examination, computed tomography scanning, magnetic resonance imaging and 5-fluorouracil assays in the blood and CSF. Importantly, the microparticle implantation was well tolerated. No acute intracranial hypertension was observed despite of the intracranial injection of 2.5 mL suspension. This can be attributed to the fast resorption of the liquid vehicle. However, the four patients who received only one single trajectory (with 1-5 deposits) experienced a transitory worsening of their pre-existing neurological symptoms. Thus, it seems to be preferable to divide the total suspension volume into several parts and to deposit them in separate trajectories. Importantly, there were no episodes of edema or hematological complications, the anticancer drug was detectable in the CSF and the median overall survival was 40 weeks (two patients survived 71 and 89 weeks, respectively).

Importantly, tumor cells express proteins that are foreign to the host because of their genetic mutations. Thus, they are vulnerable to an immune response of the human body. That is why efforts have been made to delivery immune response stimulating substances locally and in a controlled manner to brain tumors. For instance, interleukin-2 (IL-2)-loaded, gelatin- and chondroitin-6-sulfate-based microparticles have been proposed by Hanes et al. (71). Bioactive IL-2 was found to be released over at least 2 weeks in vitro; in vivo significant concentrations could be detected up to 3 weeks. The efficiency of these microparticles to protect mice challenged intracranially with B16-F10 melanoma cells is illustrated in Figure 15A (the melanoma cell challenge and microparticle injection were simultaneous). Clearly, the IL-2-loaded microparticles were able to protect the mice, whereas placebo systems were not. Interestingly, even autologous B16-F10 cells engineered to secrete IL-2 were not as effective as the controlled release microparticles. In Figure 15B, the survival curves of rats challenged intracranially with a lethal dose of 9L gliosarcoma cells are illustrated. The animals received a simultaneous injection of IL-2-loaded or drug-free microparticles. Clearly, drug-containing, controlled release microparticles were able to prolong the

Irradiated B 18 (n=19) ♦ Placebo microspheres (n=18)

-IL-2 microspheres (n=18)

ce 40

10 20

10 20

Time (days)

Control (10,000 9L)

- IL-2 microspheres

l—|—i—i—i—|—i—i—i—|—i—i—i—|—i

40 60

Time (days)

l—|—i—i—i—|—i—i—i—|—i—i—i—|—i

40 60

Time (days)

Figure 15 Efficiency of IL-2-loaded, gelatin-chondroitin-6-sulfate-based micropar-ticles to protect: (A) Mice challenged intracranially with B16-F10 melanoma. For reasons of comparison also placebo microparticles, autologous B16-F10 cells engineered to secrete IL-2, and B16-F10 cells (antigen control) were administered. (B) Rats challenged intracranially with wild-type 9L gliosarcoma cells. For reasons of comparison also placebo microparticles (control) and IL-2-loaded microparticles plus extra tumor antigen in the form of irradiated 9L tumor cells (Irr. 9L) were administered. Source: From Ref. 69.

ce 40

survival of the rats. Interestingly, the addition of extra tumor antigen in the form of irradiated 9L tumor cells (Irr. 9L) did not have any significant effect.

Was this article helpful?

0 0
How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

Get My Free Ebook


Post a comment